Yannis Paulus, MD
Associate Professor of Ophthalmology and Visual Sciences
Helmut F Stern Career Development Professor
Associate Professor of Biomedical Engineering
University of Michigan Medical
[email protected]

Dongshan Yang, PhD
Research Assistant Professor, Internal Medicine
University of Michigan Medical School

Yang Li, PhD
Associate Professor
Peking University Stem Cell Research Center

Yun Feng, MD, PhD
Chief Physician and Associate Professor of Ophthalmology
Peking University Third Hospital

JI Program: Exploratory

Project Status: Active/Ongoing

Usher Syndrome (USH) Type II is the most common type of USH, the leading genetic cause of deafness associated with blindness in the world, and there is currently no cure. Mutations on USH2A gene account for approximately 70% of USH2 cases. Gene editing can directly repair a defective gene, providing a promising therapeutic strategy for treatment of USH2A. We have developed a rabbit model carrying frameshift mutations on USH2A gene and showed early onset, progressive photoreceptor degeneration, similar to the retinitis pigmentosa (RP) symptoms observed in human patients. In parallel, we have developed an improved spCas9 variants, named meticulous integration Cas9 (miCas9), which greatly reduced both on-target and off-target insertion and deletion (indel) events and improved knock-in events by multiple folds. In this project, taking advantages of these two lines of promising work, we propose to develop an miCas9 mediated USH2A gene editing therapy in a novel USH2A rabbit model. We will use cultured rabbit fibroblasts and rabbit retina explants to optimize the CRISPR reagents, and test similar designed editing reagents in USH2A patient derived iPS cells and retinal organoids. Finally, the optimized editing reagents will be tested in vivo in the USH2A rabbit to evaluate the editing efficiency and safety of the USH2A gene editing therapy, including on- and off-target effects, biodistribution and toxicity. The long-term goal of this project is to generate data towards securing funding to further demonstrate whether miCas9 mediated gene editing can be used as a novel therapeutic strategy for treating USH2A.

Gary Smith, PhD
Professor, Molecular & Integrative Physiology
Professor, OB-Gyn and Urology
Director, MStem Cell Laboratories
Co-Director, Reproductive Sciences Program
University of Michigan Medical School
[email protected]

Liying Yan, PhD
Professor of Center for Reproductive Medicine
Peking University Third Hospital

Zhiqiang Yan, PhD
Associate Professor of Center for Reproductive Medicine
Peking University Third Hospital

JI Program: Exploratory

Project Status: Active/Ongoing

Non-invasive prenatal screening using cell-free DNA from pregnant women plasma can detect fetal trisomy’s. This yielded the hypothesis that cell-free DNA could be collected from human blastocysts produced by in vitro fertilization and used to predict the chromosome make-up of the human preimplantation embryo by ni-PGT-A. While ni-PGT-A has numerous potential clinical benefits, current literature is highly contradictory with regards to reliability and accuracy to detect embryo chromosome complement. This project aims to determine the optimal method to detect human blastocyst cell-free DNA: blastocoel sampling or spent culture media and to elucidate the concordance/discordance of individual human blastocyst chromosome status between Fertility Healthcare Provider multi-cell trophectoderm biopsy-PGT-A (FHP-PGT-A), blastocyst regional SCSeq, resulting hESC SCSeq, and blastocoel/spent media ni-PGT-A. These data will be first-in-field to address stated specific aims, and will be critical in guidance on future clinical utility of ni-PGT-A in reproductive medicine. It will also be informative about human preimplantation genetics and development and lead to mechanistic studies on chromosome copy number variance, genetic stability, and embryo development in relation to aneuploidies, normal/abnormal development, placental function, and congenital birth defects.

Jun Li, PhD
李军教授
Professor of Human Genetics
Professor & Associate Chair for Research of Computational Medicine and Bioinformatics
University of Michigan Medical School
[email protected]

Sue Hammoud, PhD
Associate Professor of Human Genetics
Associate Professor of Urology
Associate Professor of Obstetrics and Gynecology

Jie Qiao, MD, PhD
乔杰教授
President and Chief Physician
Director and Professor of the Center for Reproduction Medicine
Peking University Third Hospital
[email protected]

Peng Yuan, PhD
Assistant Professor of Obstetrics and Gynecology
Peking University Health Science Center

JI Program: Exploratory

Project Status: Active/Ongoing

Male infertility has become an increasingly severe public health crisis worldwide, yet its functional causes remain poorly understood. This project aims to study the molecular and cellular mechanisms of male germ cell development, leveraging spatial and multi-omic single-cell technologies developed by our teams. The goal is to gain deeper insights into normal spermatogenic process, and ultimately translate the knowledge to improve clinical care for infertile men. The collaborative teams will bring complementary technologies - three epigenomic measures for single cells, and high-resolution, high-content spatial mapping - to analyze healthy and diseased testis tissues, and conduct a close comparison across Chinese, European, and African American patients, which has been impossible without this collaboration. A major outcome is to generate complete catalogs of cell types and regulatory states in human testis, along with spatial organization of the seminiferous tubules at subcellular, cellular, and tissue scales. We will define differences in pathogenesis between US and China cohorts, and detect potential differences in infertility mechanism due to the maternal or paternal origin of the extra X. The study builds on rich resources already in place at our respective institutions and will bridge our two communities pursuing basic and clinical research to improve reproductive health. In future stages we will expand the collaboration to the female reproductive system and embryonic development, connecting an even wider network of colleagues and topics of medical importance.

Brian Athey, PhD
Michael Savageau Collegiate Professor & Chair
Department of Computational Medicine & Bioinformatics
Professor of Psychiatry and Internal Medicine
[email protected]

Lin Lu, MD, PhD
陆林教授
Director/ Professor, Peking University Sixth Hospital
Director/ Professor, National Institute on Drug Dependence
Peking University
[email protected]

JI Program: Exploratory

Active/Ongoing

This discovery proposal is to refine and prepare a detailed plan for a pilot clinical validation study at PKUHSC of a new pharmacogenomic/metabolomic diagnostic assay system for Bipolar Disorder-1 (BPD-1) medication selection. This project is a collaborative effort between a U-M pharmacogenomics innovator (Athey lab) and one of China’s leading psychiatric research units (Lu Laboratory). Specific plans include investigating 1) How the UM-provided PhGx test will be further refined using the Michigan Genomics Initiative (MGI) data and biospecimens for delivery to PKUHSC; 2) How a detailed SMART clinical trial will be designed by the PUHSC expert team in collaboration with the U-M team; and 3) How the U-M PhGx testing platform will be extended to analyze the relevant Han Chinese Pharmacokinetic (PK) and Pharmacodynamic (PD) genetic biomarkers and plan to test out two components of U-M PhGx test in China.

J. Brian Fowlkes, PhD
Professor of Radiology
Professor of Biomedical Engineering
[email protected]

Xiaofeng Yin, MD, PhD
殷晓峰副教授
Associate Professor of Orthopedics and Trauma
PKU People's Hospital

JI Program: Exploratory

Active/Ongoing

The goal is to develop and validate an ultrasound-based, non-invasive, portable, quantitative device that measures two critical physiological parameters in patients with critical limb ischemia (CLI): 1) volume of blood delivered to the diseased extremity through its feeding arteries; 2) adequacy of limb oxygen delivery through the difference in the oxygen content of primary feeding artery and its paired vein. Limb perfusion is of paramount importance in the patient with CLI. However, current recommended tests, such as segmental limb pressures and transcutaneous oxygen tension, are imperfect surrogates. This proposal will be the first to use a combined volume blood flow and oxygen extraction estimation system to quantitatively evaluate limb tissue metabolism in patients with CLI. The preliminary data can be used to pursue funding for large-scale trials of this methodology to assess disease level and objectively assist orthopedic and vascular surgeons in optimizing their limb salvage strategies, leading to a profound clinical impact on CLI-related vascular interventions, morbidity and mortality. In the future, this device may become a cost-effective screening tool for peripheral vascular disease and provide accurate vascular assessment prior to, during and after endovascular or surgical procedures.

Srijan Sen, MD, PhD
Frances and Kenneth Eisenberg Professor of Depression and Neurosciences
Director, Frances and Kenneth Eisenberg and Family Depression Center
Associate Vice President for Research - Health Sciences
Research Professor, Michigan Neuroscience Institute

Hongqiang Sun, MD, PhD
孙洪强教授
Director and Professor
Institute of Mental Health
Peking University Sixth Hospital

JI Program: Exploratory

Project Status: Active/Ongoing

Drs. Lu and Sun have produced a parallel sample of training physicians in China, identifying parallel problems of stress and depression among young physicians there. Here, we propose to recruit a sample of up to 1,000 last year medical students before they enter their first year of residency (as there is no internship year in China), hence at the same time point as US interns. Prior and continuing work in the US of Dr. Sen will continue and be relevant for comparison. Existing work of Drs. Lu and Sen on medical students will be highly relevant, as many of these medical students will now enter residency and are already in contact with the study. The overall objective of our research is to define contributing factors to stress-associated depression. These factors can be personal experience (childhood adversity, previous depression episodes, personal maturation during natural aging), temperamental (neuroticism score, sleep patterns and needs), genetic factors as well as situational environmental (policies governing internship structure, political events). Genetic factors in turn may affect experience and temperament. Comparing the first year of residency in China with the internship year in the US, our objective is to find both individual and internship similarities and differences. Our research will help better understand the interplay of genetic differences with environmental factors governing medical residency. This better understanding can lead to structural changes to ultimately improve the residency experience.

Chuanwu Xi, PhD
Professor of Environmental Health Sciences
U-M School of Public Health
[email protected]

Yanmei Dong, DDS, PhD
董艳梅教授
Professor and Educational Director
School of Stotamology

JI Program: Exploratory

Project Status: Active/Ongoing

Estimates suggest that pulpal disease may affect up to 30% of the world’s population. Up to 14% of endodontics therapy ends in infections within the root canal system and is difficult to treat. This project aims to establish a novel approach using nanobubble water combines with apyrase during endodontic therapy which focuses on preventing biofilm formation and reducing bacterial colonization which consequently minimizes the risk of infections post endodontics therapy. The objectives of this proposal will have a significant impact on public health by providing promising approach for endodontics therapy without changing existing endodontic procedure. We expect to decrease the post endodontics infections to less than 5% by using our novel approach.

Jason Knight, MD, PhD
Assistant Professor of Internal Medicine
University of Michigan Medical School
[email protected]

Jianping Guo, MD, PhD
郭建萍教授
Professor of Rheumatology and Immunology
Peking University Health Science Center
[email protected]

JI Program: Exploratory

Active/Ongoing

Few acquired states carry a higher risk of thrombosis than antiphospholipid syndrome (APS), a systemic autoimmune disease that impacts as many as 1-in-1000 individuals worldwide.  Neutrophil extracellular traps (NETs)—tangles of chromatin and microbicidal proteins ejected from dying neutrophils—appear to play a key role in the thromboinflammation inherent to APS.  Our Michigan Medicine team has characterized the transcriptome of APS neutrophils, where we discovered 4-fold upregulation of leukocyte immunoglobulin-like receptor A3 (LILRA3).  LILRA3 belongs to a family of surface receptors expressed especially by myeloidlineage cells, and best known for modulating HLA class I signaling.  Interestingly, the LILRA3 gene product is the only soluble receptor within the LILR family.  Another unique feature of LILRA3 is a 6.7-kb deletion polymorphism, resulting in a null allele when present.  Null-allele frequencies differ among ethnic groups:  0.560.84 (Asians), 0.17 (Europeans), and 0.10 (Africans).  Our PKUHSC team’s work in Han Asian individuals has found the null allele to be protective against rheumatoid arthritis and lupus.  This study will now be the first to characterize LILRA3 in a thromboinflammatory disorder (APS), leveraging unique expertise of Michigan Medicine and PKUHSC to (i) reveal novel APS-relevant biology, (ii) improve APS risk stratification, and (iii) lay the groundwork for future collaboration in pursuit of new APS biomarkers and therapies.

David Zacks, MD, PhD
Professor of Ophthalmology and Visual Sciences
University of Michigan Medical School
[email protected]

Liu Yang, MD, PhD
杨柳教授
Professor of Ophthalmology
Peking University First Hospital
[email protected]

JI Program: Exploratory/Ophthalmology

Status: Active/Ongoing

Retinal cell death causes vision loss in many ophthalmic diseases.  Despite improved treatments, a major knowledge gap remains in understanding the etiology, molecular mechanisms, and functional gene pathways leading to cell death. Drs. Zacks and Yang study retinal cell death in a variety of animal models, with the goal of identifying targets for the rational development of therapeutics to prevent retinal cell death and improve outcomes. Drs. Zacks and Yang will be performing proteomic analysis of the vitreous fluid of patients and perform pathway analyses in an effort to identify relevant stress-response pathways activated during retinal disease.  Pathways identified will then be validated for their contribution to cell death (or survival) in our established animal and cell culture systems. The work performed in this Discovery Award will lay the foundation for years of fruitful collaboration, with the potential to rapidly and efficiently identify and test molecular points for therapeutic intervention for preserving retinal cell viability and function – ultimately allowing for improved visual outcomes for our patients.

Aditya Pandey, MD
Associate Professor of Neurological Surgery
Associate Professor of Otolaryngology
University of Michigan Medical School
[email protected]

Yining Huang, MD
黄一宁教授
Professor of Neurology
Director, Department of Neurology
Peking University First Hospital

Program: Exploratory - Neurology

Status: Active/ Ongoing

Subarachnoid hemorrhage (SAH) is one of the most devastating forms of stroke with the highest immediate mortality of all strokes (exceeding 30%) and leading to severe disability for those who survive. This leads to a significant number of potential life years lost, creating a financial and intellectual loss to society. In addition to the initial insult, delayed cerebral ischemia (DCI) secondary to arterial vasospasm and chronic hydrocephalus requiring permanent CSF diversion are other complicating factors of subarachnoid hemorrhage. To date, aside from nimodipine, there are no preventative options for DCI or chronic hydrocephalus in SAH patients. With such strong data involving DFO use in SAH animal models and recent human data with DFO use in intracranial hemorrhage (ICH), a multicenter, randomized Phase I/II trial to determine the safety and futility of deferoxamine treatment in the human SAH population is expected provide data that changes the current treatment methodology of subarachnoid hemorrhage and improves patient functional outcomes. This proposed trial will evaluate the safety and futility of clinical deferoxamine use in SAH and could lead to changes in the current SAH treatment algorithm. If this trial is successful, it will generate crucial preliminary data that will support further clinical trial grant applications for a Phase III trial with a much larger sample size through the NIH/NINDS (USA) and National Science Foundation (China).

Alex Tsoi, PhD
Research Assistant Professor
Department of Dermatology
University of Michigan Medical School
[email protected]

Trilokraj Tejasvi, MBBS
Assistant Professor
Department of Dermatology
University of Michigan Medical School
[email protected]

Yang Wang, MD
汪旸教授
Associate Professor of Dermatology and Venereology
Peking University First Hospital
[email protected]

JI Program: Exploratory (Dermatology)

Status: Active

Summary

Cutaneous T-cell lymphoma (CTCL) is a major form of the primary cutaneous lymphomas and affects all populations in the world including the American and Chinese. CTCL symptoms range from mild itchy red patches to large, painful, disfiguring nodules, and patients with the advanced stages of CTCL only have up to a 50% three-year survival rate. CTCL patients respond differently to current available treatments, and the subtypes (e.g. Sezary syndrome) vary greatly in their relapse-rate and prognosis. While we and others have conducted population-specific genetic, epidemiological, and/or molecular studies, there has not been any cross-ethnic study to systematically evaluate the shared/unique risk factors associated with prognosis cross populations. With CTCL being an uncommon cancer with limited armamentarium in management, it is imminent to identify robust prognosis biomarkers. This project will set forth the first collaboration between the Michigan Medicine Department of Dermatology and the PKUHSC Department of Dermatology, as well as Venereology from the Peking University First Hospital, drawing on the unique resources and the expertise of the investigators from the two institutions. First, we have a large Chinese CTCL cohort in PKUHSC with records and/or samples from >600 patients. Second, UMHS and the Dermatology clinics have access to >1,400 CTCL patients’ medical records, and we also banked the biopsies with various immunophenotypes of these patients. Thirdly, we have vast experience in statistical and omics analysis for assessing disease outcomes, including in-house bioinformatics pipelines developed in the Michigan Medicine Center for Cutaneous Bioinformatics.

Margit Burmeister, PhD
Research Professor, Molecular & Behavioral Neuroscience Institute
Professor of Computational Medicine & Bioinformatics
Professor of Human Genetics, Professor of Psychiatry
Co-Director, Bioinformatics Graduate Program
[email protected]

Jingmin Wang, MD, PhD
王静敏教授
Professor
Department of Pediatrics
Peking University First Hospital
[email protected]

JI Program: Exploratory (Human Genetics)

Status: Active/ Ongoing

Intellectual disability/development delay (ID/DD) is a common group of neurodevelopmental disorders characterized by substantial limitations in both intellectual functioning and adaptive behavior, starting before the age of 18 years with a prevalence of 1%~3%. Genetics is known to have an important role in etiology of ID/DD. Discerning the precise genetic causes for specific ID/DD patients will inform prognosis, management and therapy, enables access to disorder-specific support groups, and facilitates family planning. Specific knowledge of the genetic basis of disease may in some cases also lead to direct therapeutic interventions. Trio-based whole exome sequencing (WES) has become the best option to identify genetic causes of ID/DD. Although rare variants in more of >700 different genes have now been shown to be associated with ID/DD, many disease-causing genes still remain to be discovered. The respective research teams have already collaborated on genetic analysis of trio-based WES results of 20 families with ID/DD & hypomyelination leukodystrophy (HLD). Eight candidate novel genes related to ID/DD&HLD have been identified. Of these, TMEM106B, has just been published in Brain, and follow-up is underway on two other strong candidates: CSMD3 and TMEM63A. These preliminary data strongly support our overarching goal of this project: to identify and further study genetic causes of ID/DD&HLD patients. First, we propose to discover novel disease-causing genes through trio-based WES of 50 Chinese ID/ DD&HLD families in whom there is a high clinical suspicion for an underlying genetic disorder. Our approach will benefit from prior collaboration of the two teams on HLD, a more specific sub-phenotype within the ID/DD spectrum. Second, taking advantage of the candidate novel genes identified through in prior collaboration, the mutation effect of candidate variants will be evaluated in patient-derived skin fibroblasts and in CRISPR/Cas9-edited human embryonic stem cell already transgenic for neurogenin2 (Ngn2), allowing use of a newly developed rapid neurogenesis method by forced expression of Ngn2 in stem cells (SCs), in cooperation with U-M’s Human Stem Cell and Genome Editing core facility. Establishing neuronal cell lines for promising candidate gene variants will provide a cellar platform for pathogenesis studies and in-vitro drug screens.

John DeLancey, MD
Norman F Miller Professor of Gynecology
Professor of Obstetrics and Gynecology and Professor of urology
University of Michigan Medical School
[email protected]

Jianliu Wang, MD, PhD
王建六教授
Chairman and Professor
Department of Obstetrics & Gynecology
Vice President
Peking University People's Hospital
[email protected]

JI Program: Exploratory (Ob/Gyn)

Status: Active/ Ongoing

Summary

Pelvic organ prolapse (POP) afflicts from 13.1 to 25.9% of women in China and the U.S. so severely that it requires surgery in ~230,000 American women per year, with a 25% surgical failure rate even in best hands. The successful, complication-free, treatment of this problem is one of the biggest challenges facing urogynecologists today. Considering the aging population, this would become not only a medical issue but a social problem as well. The pathomechanism of pelvic organ prolapse is complex and involves multiple structures. The lack of the ability to identify the specific structure failure sites in the complex muscular and connective tissue apparatus leading to her prolapse also limits our ability to understand operative failure and hinders the effective surgical planning and treatment innovation. Recently, UM investigators have for the first time developed cutting-edge techniques combining “3D Stress MRI” with biomechanical structural analyses to identify failure mechanisms —ushering in a new era of pelvic floor science. Shifting from empirical treatment management to treatment based on biomechanics-informed precision medicine and surgical planning could greatly advance the field of the prolapse surgery just as significantly as the introduction of echocardiography changed of treatment congestive heart failure. This will benefit all the women and their descendants in the U.S. and nationwide population in China.

Outcome

• To date, a total of 67 subjects from both sides were enrolled. A protocol has been established between Michigan Medicine and PKUHSC to transfer and share de-identified MRI data. 
• The newly acquired high-resolution MRI allows the detailed study of Level III anatomical structures and their connections. For example, perineal membrane as a key structure in Level III support can now be reconstructed as 3D model based on living women's anatomy. We developed the measurement scheme allows structure hypothesis being tested. This work has been selected as Best Clinical/Non-Surgical Abstract and will be presented in Joint Scientific Meeting 2019, entitled "MR- Based Perineal Membrane Quantification in Nulliparous and Parous Women With and Without Prolapse: Technique Development".
• We developed the technique to reconstruct Level III Pelvic Floor "Connectome" and demonstrate our ability to reconstruct these structures in both women with and without injury/prolapse. This work has been submitted to international conference (AUGS/IUGA 2019) and has been selected as long podium presentation, titled as "The Level III Pelvic Floor "Connectome": Technique development and proof of concept "accepted as long podium presentation" and Preliminary Findings".

Asheesh Bedi, MD
Harold W and Helen L Gehring Early Career Professor of Orthopaedic Surgery
University of Michigan Medical School
[email protected]

Tristan Maerz, PhD
Research Investigator
Orthopaedic Surgery
University of Michigan Medical School
[email protected]

Yingfang Ao, MD
敖英芳教授
Professor and Director
Institute of Sports Medicine
Peking University Third Hospital
[email protected]

JI Program: Exploratory (Orthopedics)

Status: Active/ Ongoing

Summary

In efforts to study the pathoetiology of post-traumatic osteoarthritis (PTOA), we propose a collaborative, prospective cohort study of 38 patients undergoing primary anterior cruciate ligament (ACL) reconstruction after ACL rupture. We will assess the longitudinal progression of patient-reported outcomes, knee laxity, MRI-based articular cartilage morphology and composition, and serum-borne biomarkers of cartilage degeneration up to 1 year of follow-up. Furthermore, stem cell mobilization, chemokine and pro-inflammatory cytokine concentrations, and inflammatory cell recruitment into synovial tissue will be measured from intraoperatively-collected samples. We will perform mixed multivariate linear regression modeling to elucidate potentially novel relationships between patient demographics, anatomy, biological factors, and downstream alterations in articular cartilage morphology and composition. 

J. Scott VanEpps, MD, PhD
Assistant Professor of Emergency Medicine
University of Michigan Medical School
[email protected]

Ya'an Zheng, MD
郑亚安教授
Professor of Emergency Medicine
Peking University Third Hospital
[email protected]

JI Program: Exploratory (Emergency Medicine)

Status: Active/ Ongoing

Summary

There are 19 million world-wide cases of sepsis with more than a million in the U.S. Rapid administration of appropriate antibiotics is the key to reducing morbidity and mortality. However, blood cultures – the gold standard for diagnosis, pathogen identification and antibiotic susceptibility testing (AST) –are limited by long time to result (>48hrs), low sensitivity and specificity, and limited viral or fungal identification. In almost all cases, patients are started on empiric antibiotics design to cover most but not all of the most likely pathogens. This one-size-fits-all use of antibacterial drugs leads to antibiotic resistance, severe side effects or under-treatment of critically ill patients. We have developed a novel, ultrasensitive, polymerase chain reaction (PCR) detection system that couples standard PCR primers to gold nanorods (NR-PCR). This method is at least 50 times more sensitive than the most sensitive PCR detection techniques currently available. The collaboration established between Michigan Medicine and Peking University Health Science Center provides a unique opportunity for this and future projects. Beyond accelerating the translation and adoption of a novel microbiological diagnostic, this partnership will (1) reveal variations in practice patterns between the two institutions regarding diagnosis of suspected bloodstream infection; (2) increase the power and generalizability of this study by expanding the size and diversity of the patient cohort for assay testing; (3) provide access to an at risk patient population where antibacterial resistance is rapidly growing (i.e., in China); and (4) establish an infrastructure foundation for future international studies of sepsis diagnostics and potential therapeutics.

Outcome

• We have demonstrated that the ultra-sensitivity of the NR-PCR technology can be translated to the detection of bacteria and antibiotic resistance.  Assuming the assay can be optimized now for reliability/reproducibility this will have tremendous impact on the time to diagnosis of patients with suspected bacterium. The time to result for this assay remains less than 3 hours which is a dramatic improvement of standard therapy which can exceed 48 hours.

Gary Smith, PhD
Professor, Molecular & Integrative Physiology
Professor, OB-Gyn and Urology
Director, MStem Cell Laboratories
Co-Director, Reproductive Sciences Program
University of Michigan Medical School
[email protected]

Jie Qiao, MD, PhD
乔杰教授
President and Chief Physician
Director and Professor of the Center for Reproduction Medicine
Peking University Third Hospital
[email protected]

JI Program: Exploratory (Ob/Gyn)

Status: Active/ Ongoing

Summary

The incidence of human embryo aneuploidy (abnormal number of chromosomes) is more prevalent than other mammals and the primary cause of spontaneous miscarriages, congenital birth defects and infertility. Infertility affects 1 in 6 reproductive age couples in the United States, China, and Worldwide. While success in treating infertility has increased over the last 3 decades, the current National/International average success in having a baby with Assisted Reproductive Technologies (ARTs), like In Vitro Fertilization (IVF), is ~35% across all maternal ages. In addition, this average IVF-live birth success declines dramatically in women older than 37 years of age. This is believed to be caused by increased frequency of oocyte meiotic non-disjunctions in the first and second oocyte meiotic divisions prior to embryo development. In the last decade significant efforts have been applied to improve clinical ART success rates by performing genetic analysis of the human pre-implantation embryo.

Experiments proposed in the study utilize individual and collaborative strengths of the Smith lab at University of Michigan / MStem Cell Lab and the Qiao lab at Peking University Health Science Center. The Smith lab will bring well-established regulatory compliance and implementation of human embryo donation for human embryonic stem cell derivation and research. The Smith lab also brings extensive expertise in human pre-implantation embryogenesis, micromanipulation, human embryo outgrowth, and human embryonic stem cell derivation and analysis. The Qiao lab will bring vast experience also in human embryology, and importantly in single-cell genetic analysis and state-of-the-art genetic sequencing and bioinformatics. Collectively, data generated through this mutually beneficial inter-university collaboration will begin to provide basic information about early human embryo cell specification, genetic stability of mosaicism during early human embryo development, mechanistic causes of congenital aneuploidies, and practical information about safety and efficacy of clinical pre-implantation genetic screening.

Outcomes

• 1 faculty member and 1 PhD student from PKUHSC received extensive training for 1 year and 3 months respectively at Dr. Smith's lab in U-M. Specific training received includes: embryo vitrification/ warming, embryo biopsy, embryo plating, initiation of hESC derivation, hESC expansion.
• PKUHSC visiting scholars shared expertise in single cell isolation, and MALBAC whole genome amplification, resulting in standardized protocols in both areas at U-M.
• Dr. Gary Smith visited PKUHSC in January 2018 and April 2019, with successful data assessment and discussion with the PKUHSC team.
• An abstract (which resulted in an oral presentation) was submitted and accepted at the American Society of Reproductive Medicine (ASRM) meeting in Denver, October 2018.
• U-M team invited the PKUHSC PI, Professor Jie Qiao, to be a presenter at the International Meeting on Genetics of Assisted Reproductive Technologies, where Dr. Smith also presented preliminary findings from the JI collaborative project. 
• PKUHSC is developing additional bioinformatics/ in silico assessment protocols determining copy number variance (CNV).

Frederic Blow, PhD
Professor of Psychiatry
Director, Addiction Center
Director, Substance Abuse Program
University of Michigan Medical School
[email protected]

Mark Ilgen, PhD
Professor, Department of Psychiatry
Director, University of Michigan Addiction Treatment Services
Associate Director for Adult Research, Addiction Center
University of Michigan Medical School
[email protected]

Lin Lu, MD, PhD
陆林教授
Director/ Professor, Peking University Sixth Hospital
Director/ Professor, National Institute on Drug Dependence
Peking University
[email protected]

JI Program: Exploratory (Psychiatry)

Status: Active/ Ongoing

Summary

In both the United States (US) and China, substance use disorders (SUDs), particularly addiction to alcohol, tobacco and opiates, are significant public health problems despite substantial research resources devoted to understanding their causes, consequences and treatment. Two of the largest addictions research groups in each country are located at the University of Michigan [UM; which is one of the top institutions in the US in terms of total funding from National Institute on Drug Abuse (NIDA)] and Peking University [PKU; which houses the National Institute on Drug Dependence]. However, prior to the start of this project, information-sharing and research on addiction between these two institutions has been limited. This UM-PKU Discovery Award is designed to foster collaborations between addictions researchers at these two institutions with the goal of building the foundation for future research collaborations. Through regular ongoing team meetings via WeChat, travel by investigators in each direction for in-person meetings, and integration of early-career investigators in projects and meetings, this collaboration will evolve and expand during the funding period. In addition, this project will focus on addressing the topic of co-occurring pain and addiction. This project is important, because, despite research highlighting the unique importance of SUDs and pain by the proposed research team, few international collaborations exist between these researchers. Refining a novel behavioral treatment for co-occurring pain and addiction will make a significant impact because it could (1) decrease pain and substance use, (2) improve quality of life, and (3) decrease the costs to society of poorly managed pain and SUDs. This work will lay the groundwork for future funded joint research by UM and PKU faculty.

Lori L. Isom, PhD
Chair, Department of Pharmacology
Maurice H. Seevers Collegiate Professor of Pharmacology
Professor of Molecular and Integrative Physiology
Professor of Neurology
University of Michigan Medical School
[email protected]

Yuwu Jiang, MD, PhD
姜玉武教授
Director of Department of Pediatrics
Director of Pediatric Epilepsy Center
Peking University First Hospital
[email protected]

JI Program: Exploratory (Pharmacology)

Status: Active/ Ongoing

Summary

The overarching goal of the Isom and Jiang laboratories is to understand the molecular basis of genetic epilepsy. Our objective here is to combine the expertise of our two research groups to discover novel epilepsy mutations in potassium channel genes and to understand their contributions to neuronal hyperexcitability in order to provide useful platforms for future drug discovery. Potassium channels, encoded by more than 90 genes, are the largest ion channel family. Potassium channel proteins are critical to the establishment and maintenance of neuronal excitability in brain, and thus it is not surprising that mutations in potassium channel genes are important factors in epileptogenesis in human patients, especially in pediatrics. Clinical studies have identified 17 potassium channel gene mutations linked to epilepsy, including pediatric epileptic encephalopathy. Studies of cellular and animal models predict that additional potassium channel genes will be implicated in human epilepsy. Understanding the effects of these mutations on channel function and on brain network excitability is critical to the successful development of novel therapeutics in the future.

Yongqing Li, MD, PhD
李永庆教授
Assistant Professor of Surgery
University of Michigan Medical School
[email protected]

Baoguo Jiang, MD
姜保国教授
Professor of Orthopedics and Traumatology
Peking University Health Science Center

JI Program: Exploratory (Trauma Surgery)

Status: Completed

Summary

Injury is a leading cause of death and disability for all age groups, causing around 5 million deaths worldwide each year. Sepsis accounts for approximately 215,000 deaths and over 751,000 hospitalized cases annually, with an estimated economic burden of $16.7 billion in the U.S. Both injury and sepsis experience an identical systemic inflammatory response syndrome (SIRS) in the early stage, but the treatment for these conditions are very different. To date, there is no effective method to differentiate SIRS from sepsis, which leads to either delays in treatment for sepsis or unnecessary use of antibiotics for SIRS. Obviously, a key requirement for accurately treating these life threatening illnesses is to distinguish sepsis from other forms of SIRS at an early time point. Recently citrullination of histones by nuclear localized Peptidylarginine deiminase (PAD) has been identified as an early step in a new type of cell death termed NETosis. It is known that histone H3 citrullination serves as a convergence point for diverse inflammatory signals that trigger the neutrophil response to infections. Effective control of histone post-translational modifications (PTMs), such as citrullination, represents a promising approach for both diagnosis and treatment. The objectives of this study will be carried out by Michigan Medicine and PKUHSC corporately: 1) Michigan Medicine will generate anti-citrullinated histone H3 monoclonal antibody (CitH3 mAb) and evaluate the antibody with or without PAD inhibitors in animals; and 2) PKUHSC will assess values of CitH3 in blood and neutrophils of septic patients. The accomplishment of the study will serve as a milestone in our long term goal to regulate histone PTMs by small molecule inhibitors as a viable clinical approach for preventative and therapeutic treatment of trauma and sepsis.

Outcomes

• Successfully identified reliable biomarker CitH3 for clinical sepsis. Study showed that inhibition of PAD with pan-PAD inhibitor can significantly improve survival.
  Antibody against CitH3 has led to 2 patent submissions; both are under review:
  1. CitH3 as a diagnostic tool (China)
  2. CitH3 as a therapeutic tool (U.S.)
• A potential clinical trial could be implemented in China after obtaining CitH3’s diagnostic patent approval.
• 3 faculty and students from PKUHSC visited Michigan Medicine for extensive training at Dr. Alam’s lab.

Publications

1. Zhao T, Pan B, Alam HB, … Li Y. (2016) Protective effect of Cl-amidine against CLP-induced lethal septic shock in mice. Sci Rep. 2016;7;6:36696.
2. Pan B H, Alam HB, Chong W, … Li Y. (2017). CitH3: a reliable blood biomarker for diagnosis and treatment of endotoxic shock. Scientific Reports. 2017;7, doi:10.1038/s41598-017-09337-4.
3. Liang Y, Pan B, Alam HB, Deng Q, Wang Y, Chen E, Liu B, Tian Y, Williams A, Duan X, Wang Y, Zhang J, Li Y. Inhibition of peptidylarginine deiminase alleviates LPS-induced pulmonary dysfunction and improves survival in a mouse model of lethal endotoxemia. Eur J Pharmacol. 2018 Jul 4. pii: S0014-2999(18)30372-8. doi:10.1016/j.ejphar.2018.07.005. [Epub ahead of print].

Kyle Gunnerson, MD, FCCM
Associate Professor
Director, Emergency Critical Care Center
Department of Emergency Medicine
University of Michigan Medical School
[email protected]

Qingbian Ma, MD
马青变 教授
Chair of Emergency Medicine
Peking University Third Hospital

JI Program: Exploratory (Emergency Medicine)

Status: Active/ Ongoing

Summary

Dedicated emergency department critical care units are well-established in China but novel to the U.S. The recent establishment of an emergency department Critical Care Center (EC3) at the main University Hospital of Michigan Medicine provides a unique opportunity for clinical research collaboration with the well-established Emergency Department Resuscitation Unit and Intensive Care Unit (ED-RU-ICU) at Peking University 3rd Hospital. Innovative strategies for early diagnosis and treatment of time-sensitive critical illness and injury could be co-developed and rapidly evaluated. However, a major challenge to collaborative multicenter research in emergency critical care is the lack of validated tools to risk-adjusted outcomes. The overall goal of this research collaboration is to develop a clinical research platform that will facilitate future multicenter interventional clinical trials in the emergency critical care setting.      

Outcome

• Proposed enrollment numbers:1500 from each sit. Actual enrollment numbers: U-M: 3,543 and PKUHSC: 1,706.
• Three PKUHSC visiting scholars shadowed in the EC3/ ED at Michigan Medicine in 2017 and 2018
• Observed 30-day mortality in the study cohort was 14.3% (508/3543) for the U.S. population and 17.8% (303/1706) in the Chinese population (p= 0.0015).
• Results were presented at two national critical care conferences in the U.S.:
  1. Joshua M. Glazer, Kyle J. Gunnerson, Richard P. Medlin, Steve L. Kronick, Robert W. Neumar, and Benjamin S. Bassin: PReDICT: Prognosticate Resuscitation Demands Integrating Computerized Triage, SAEM Annual Meeting, Academic Emergency Medicine, 23, Suppl. 1, S237, 2016.
  2. Joshua Glazer, Richard Medlin, Benjamin Bassin, Kyle Gunnerson: Existing Disease Severity Scoring Systems and Their Utility in an ED- ICU, 46th Annual Critical Care Congress, Honolulu, Hawaii, Critical Care Medicine, 44(12) Supplement 1, 356, 2016.

Publications

One collaborative manuscript was submitted in early June 2019 to the Journal of Critical Care Medicine (title: "Risk-adjusted Outcome Prediction Tool for Emergency Department Intensive Care Unit Patients".

Margit Burmeister, PhD
Research Professor, Molecular & Behavioral Neuroscience Institute
Professor of Computational Medicine & Bioinformatics
Professor of Human Genetics, Professor of Psychiatry
Co-Director, Bioinformatics Graduate Program
[email protected]

Ming Li, MD
李明教授
Professor
Department of Pediatrics
Peking University First Hospital
[email protected]

JI Program: Exploratory (Psychiatry)

Status: Active/ Ongoing

Summary

Cognitive and social-emotional impairments are a pressing public health concern, as they compromise school and job performance and personal relationships in millions of individuals in the U.S. and globally. Understanding early origins of such impairments and identifying potentially modifiable factors are a high priority. Epigenetic effects are reported for prenatal environmental exposure such as lead (Pb), pesticides, bisphenol A, and stress and nutrient deficiencies, such as folate or iron deficiency (ID). Most studies consider single exposures. However, exposure to mixtures of environmental toxicants, nutrient deficiencies or harmful dietary additives, and stressors is common. This pilot study will explore epigenetic changes and neurodevelopmental outcome with real-life prenatal exposures (mixtures of pesticides, Pb, and ID). The overarching hypothesis is that exposure mixtures change offspring DNA methylation patterns of key neurodevelopmental genes/ pathways related to poorer neurocognitive function later in life. The study builds on NIH-funded projects on neurodevelopmental impacts of pre- and post-natal environmental exposures and ID, involving a cohort of 1,600 full-term infants from a rural area near Beijing. Parent study measures of environmental exposures, iron status, growth, behavior, sensory systems, and motor and cognitive function were collected at birth/ 6 weeks, 9 and 18 months. Over 200 pesticides are assayed in cord blood, as well as heavy metals. Cord blood samples have been saved frozen for genetic and epigenetic analyses. The findings of this and future full-scale studies may point to avenues for intervention to prevent or ameliorate adverse neurodevelopmental effects of real-life prenatal exposure mixtures and nutrient deficiencies.

Qian Dong, MD
董倩教授
Associate Professor, Radiology
Director, Medical Student Education
Musculoskeletal Division
University of Michigan Medical School
[email protected]

Jin Lu, MD
路瑾教授
Professor of Medicine and Hematology
Peking University People's Hospital

JI Program: Exploratory (Radiology)

Status: Active/ Ongoing

Summary

Multiple myeloma (MM) is the second most common hematologic malignancy affecting terminally differentiated plasma cells. Despite advances in multi-modality therapy, patients with myeloma live on an average of five to seven years. The development of new therapies has resulted in improved outcomes for patients with MM; yet, there is an unmet clinical need to develop systemic and non-invasive imaging biomarkers in accurate staging and quantitative treatment response assessment in MM, allowing the optimizing therapy for individual patients, and improving patient care. This collaborative project seeks to discover clinically translatable magnetic resonance imaging (MRI) metrics that would provide a predictive biomarker to stage and assess treatment response in MM. The computerized image analysis and quantification methods with MRI (conventional MRI and diffusion MRI) will be useful as a clinical decision support system at the time of baseline examination, and subsequently for quantitative imaging, treatment response monitoring, and prognosis prediction. Quantitative data from computerized image analysis and MRI should improve the accuracy and efficacy of the staging and the assessment of treatment response for multiple myeloma. The specific aim of this project is to investigate the ability of 3D dynamic intensity entropy transformation (DIET) enhanced MRI and diffusion-weighted MRI (DW-MRI) for assessing treatment response in multiple myeloma that correlates with clinical outcome, and establish to what extent DIET enhanced and diffusion MRI predict treatment response in myeloma patients.

Outcome

• A total of 50 subjects were recruited from PKUHSC, with 35 recruited at Michigan Medicine.
• Based on preliminary data, our hypothesis is that the development of noninvasive imaging biomarkers from quantitative  image analysis of multiple MRI sequences, in combination with clinical biomarkers, will improve the accuracy and efficacy of staging and assessment of treatment response for MM.
• Data from this research will lay the foundation for a larger scale clinical trial to definitively test the hypothesis, which will enable quantitative staging, treatment response monitoring, and prognosis prediction.

Publication

1. Zhou C, Chan H-P, Dong Q, Couriel DR, Pawarode A, Hadjiiski LM and Wei J. Quantitative analysis of MRI for assessment of treatment response for patient with multiple myeloma using dynamic intensity entropy transformation (DIET) method: a preliminary study. Radiology. 2015 Jul 20:142804. PMID: 26192897.