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

Tianbing Wang, MD
王天兵教授
Professor of Surgery
Peking University Health Science Center
[email protected]

JI Program: Pulmonary

Status: Active/Ongoing

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening diseases in critically ill patients that continue to increase rapidly. Disease incidence is projected to increase to 335,000 cases/year by 2030, with deaths nearly doubling to 147,000 deaths/year. Treatment of patients typically consists of supportive positive pressure ventilation, as no effective targeted therapy currently exists. Severe sepsis is the most common (33-46%) risk factor for ALI/ARDS. To enable discovery of new specific therapeutic targets and to effectively manage sepsis-induced ALI/ARDS (sepsis-ALI/ARDS), a better understanding of injury-causing pathogenic mechanisms is required.  An emerging theory of sepsis-induced ALI (sepsis-ALI) and ARDS (sepsis-ARDS) is that lung damage is due to the release of nuclear proteins from cell death such as neutrophil extracellular traps (NETs) and pyroptosis in the host response to infection. We have discovered that citrullinated histone H3 (CitH3), a subtype of histones, is a significant mediator of sepsis pathogenesis, which was previously unrecognized. Our clinical preliminary data show that CitH3, citrullinated by peptidylarginine deiminases 2 and 4 (PAD2 and PAD4), is also an important biomarker of sepsis-ARDS. The CitH3 levels in plasma and bronchoalveolar lavage (BAL) are increased only in patients with infectious ARDS but not with non-infectious ARDS. In mice, CitH3 induces macrophage pyroptosis. Our central hypothesis is that infection causes neutrophils to release NETs and CitH3, and high levels of CitH3 induce pyroptosis, resulting in the death of alveolar macrophages and epithelial cells; CitH3 is also a biomarker that can distinguish levels of severity in sepsis-ARDS and can aid clinical management. We recently generated a novel CitH3 mouse monoclonal antibody which reduces ALI and improves survival significantly in mouse sepsis models. Our project is to develop a humanized CitH3 antibody and explore the new intervention for diagnosis/ treatment of patients with sepsis-induced ALI/ARDS.  We will evaluate the mechanism and clinical significance of CitH3 in sepsis-ALI/ARDS. Accomplishment of the proposed studies will considerably advance the field by revealing the potentially crucial role that CitH3 plays in sepsis-ALI/ARDS, which may disclose novel therapeutic targets that could lead to new therapies to ameliorate sepsis-ALI/ARDS.

Venkat Keshamouni, PhD
Associate Professor
Pulmonary and Critical Care Medicine
Department of Internal Medicine
University of Michigan Medical School
[email protected]

Jun Wang, MD, PhD
王俊教授
Professor, Director, Department of Thoracic Surgery
Peking University People's Hospital
[email protected]

JI Program: Pulmonary

Status: Active/ Ongoing

Summary

Lung cancer is the leading cause of cancer mortality worldwide. Use of immune-checkpoint blockers has yielded impressive clinical benefit, but only in a subset of patients. Recent studies demonstrate that the expression of the checkpoint-ligands like PDL-1 on host cells, rather than on cancer cells, determines the efficacy of checkpoint-blockade in mice. A number of host immune cells, including NK cells, express PDL-1 and could dictate the efficacy of checkpoint-inhibitors in humans. A recent phase I/II study combining anti-KIR (an inhibitory NK cell receptor) antibody with anti-PD1 antibody in head & neck cancer showed a dramatic 24% objective response rate over 13.3% with anti-PD1 alone. Epithelialmesenchymal transition (EMT) is a transdifferentiation process by which epithelial cancer cells acquire migratory and invasive capabilities to metastasize. We demonstrated that a 20-gene EMT-signature is predictive of survival in non-small cell lung cancer (NSCLC) patients. More recently, we showed that EMT-induced expression of a cell-adhesion molecule CADM1 renders cancer cells more susceptible to NK cytotoxicity and inhibits metastasis. This proposal will test whether boosting NK cell functions can control metastasis and whether the EMT signature can be predictive of anti-tumor efficacy of NK cell therapy, as well as response to checkpoint-blockade therapy in NSCLC. These studies will provide proof-of- principle for a potential phase I/II study for proposed NK cell-based strategies, along with the support to the potential of EMT-signature and NK cell phenotype in predicting response to checkpoint-blockade and pave the way for subsequent mechanistic studies.

Robert Dickson, MD
Assistant Professor
Pulmonary and Critical Care Medicine
Department of Internal Medicine
University of Michigan Medical School
[email protected]

Ning Shen, MD
沈宁教授
Associate Director of Pulmonary Division
Vice President
Peking University Third Hospital
[email protected]

JI Program: Pulmonary

Status: Active/ Ongoing

Summary

Ventilator-associated pneumonia (VAP) is a tremendous cause of morbidity, mortality, and healthcare expense in China and the United States. Clinical identification of respiratory pathogens still relies on the culture-based techniques used by Pasteur in the 1880s. Delayed identification of pathogens in pneumonia results in increased morbidity and mortality, and indiscriminate use of broad empiric antibiotics impedes antimicrobial stewardship. This novel study will extend recent discoveries in molecular microbiology to the rapid detection of pathogens in VAP. The long-term objective of this proposal is to accelerate the identification and quantification of pathogens in VAP using novel, real-time molecular technologies. In Objective 1, we will develop a protocol and pipeline that will rapidly identify respiratory pathogens in four hours via real-time metagenomics. In Objective 2, we will develop a protocol and determine reference ranges that will rapidly quantify respiratory pathogens in two hours using a novel ultrasensitive PCR platform.

Andrew Chang, MD
John Alexander Distinguished Professor of Thoracic Surgery
Associate Professor of Surgery and Section Head
Thoracic Surgery Section
Department of Surgery
University of Michigan Medical School
[email protected]

Qiao Li, PhD
Research Associate Professor
Department of Surgery
University of Michigan Medical School
[email protected]

Jixian Liu, MD
刘继先教授
Deputy Director, Department of Thoracic Surgery
Peking University Shenzhen Hospital

JI Program: Pulmonary

Status: Active/Ongoing

Summary

Tumor infiltrating lymphocytes (TILs) comprise a subset of white blood cells isolated from the tumor and surrounding parenchyma that are thought to mediate tumor-specific immune responses. Autologous TIL cultures, isolated from resected tumor tissue, expanded ex vivo and subsequently reinfused into the preconditioned donor patient, have been shown to elicit durable response rates with some instances of long-term survival. In contrast, another subset of TILs appears to attenuate clinical response. We hypothesize that TILs which recognize tumor-specific neoantigens originate from somatic mutations and are more effective in eliciting a clinically significant response. As proof of concept, it has been shown that TILs harvested from resected metastatic lung tumors from a subject with metastatic colorectal carcinoma recognized neoantigens generated by the mutant KRAS-G12D. Re-infusion of expanded TILs led to a significant antitumor response in this subject. The aim of our study is to utilize high throughput sequencing and tetramer flow cytometry to identify tumor-specific neoantigens derived from patients with non-small cell lung carcinoma, both adenocarcinomas and squamous cell carcinomas, as a prelude to the treatment of NSCLC patients with autologous T cells.

Theodore J Standiford, MD
Professor of Internal Medicine (Emeritus)
University of Michigan Medical School
[email protected]

Bei He, MD
贺蓓教授
Professor of Pulmonary Medicine
Director of Respiratory Diseases Center
Peking University Third Hospital
[email protected]

JI Program: Pulmonary

Status: Active/ Ongoing

Despite the high prevalence of chronic obstructive pulmonary disease (COPD), there continues to be a large gap in our understanding of disease pathogenesis and mechanisms accounting for large variability in disease phenotype. Untargeted metabolomics is an ideal approach to uncover the metabolic basis of disease, as well as discover unique drug target opportunities aimed at these nodal metabolic drivers of disease. There are very limited data from metabolomics studies from plasma/ serum and exhaled breath condensate that suggest certain metabolic pathways or metabolites might predict the presence and/or severity of COPD phenotypes. We hypothesize that: 1) smokers with COPD will have a metabolomics signature that is distinct from healthy non-COPD smokers; 2) this signature will be associated with clinically relevant manifestations of disease (e.g., GOLD classification, PFT); and 3) metabolomics signatures will be race-specific. The availability of biosamples from a well-characterized population of smokers with and without COPD, combined with our established in-house metabolomics expertise, will allow us to robustly test these novel hypotheses.

Outcomes

• Patient recruitments were successfully completed at PKUHSC and Michigan Medicine. Samples of both BAL and serum from PKUHSC were transferred to Michigan Medicine for analyses.
• Metabolomics analyses on both PKUHSC cohort and US Spiromics cohort were completed.
• 1 PhD student and 1 faculty from PUHSC received extensive training at Michigan Medicine, mentored by Drs. Stringer, Han and Standiford.

Publications

1. Wenqi Diao, MD; Wassim W. Labaki, MD; MeiLan K. Han, MD; Larisa Yeomans, PhD; Yihan Sun, PharmD; Zyad Smiley, BS; Jae Hyun Kim, BS; Cora McHugh, BS; Pingchao Xiang; Ning Shen, MD; Xiaoyan Sun; Chenxia Guo; Ming Lu, MD; Theodore J. Standiford, MD; Bei He, MD; Kathleen A. Stringer, PharmD. Disruption of histidine and energy homeostasis in chronic obstructive pulmonary disease (submitted; International Journal of COPD).
2. Wassim W. Labaki, Tian Gu, Susan Murray, Jeffrey L. Curtis, Larisa Yeomans, Russell P. Bowler, R. Graham Barr, Eric A. Hoffman, Alejandro P. Comellas, Nadia N. Hansel, Christopher B. Cooper, Richard E. Kanner, Robert Paine III, Gerard J. Criner, Mark T. Dransfield, Merry-Lynn N. McDonald, Jerry A. Krishnan, Eugene R. Bleecker, Stephen P. Peters, Prescott G. Woodruff, Wanda K. O’Neal, Wenqi Diao, Bei He, Fernando J. Martinez, Theodore J. Standiford, Kathleen A. Stringer*, MeiLan K. Han*. Serum amino acid concentrations and clinical outcomes in smokers: SPIROMICS metabolomics study (in revision, Nature Communications).

Grants:

1. NIH/NHLBI K23 (Labaki, W.) Metabolomic alterations in patients with COPD. Submitted in June 2019. Under review.
2. NIH R01 (Standiford, T., Li, Y). Submitted in June 2019. Under review.

Steven Huang, MD
Associate Professor
Pulmonary and Critical Care Medicine
Department of Internal Medicine
University of Michigan Medical School
[email protected]

Yahong Chen, MD
陈亚红教授
Deputy Director, Department of Pulmonary and Critical Care Medicine
Department of Research Administration
Peking University People's Hospital

JI Program: Pulmonary

Status: Completed

Asthma is one of the most common lung diseases worldwide, with the prevalence, especially in low and middle-income countries, increasing every year for the past decade. The prevalence of asthma in China has risen sharply coinciding with an increase in ambient air pollution, a well-known risk factor for the development of asthma. Although epidemiologic data support a strong link between air pollution and asthma prevalence, the pathologic mechanisms by which pollution contributes to asthma, and in particular asthma severity, are poorly understood. This project seeks to understand the extent to which asthmatic patients in China are affected by ambient air pollution, and determine how epigenetic mechanisms contribute to the ability of air pollution to worsen asthma severity. The investigators aim to: 1) determine how longitudinal exposure to particulate matter contributes to both DNA methylation changes of specific genes and to worsening symptoms, decline in physiology, and increase in frequency of asthma exacerbations of adults with moderate-to-severe asthma in China; and 2) determine the mechanism by which particulate matter alters the DNA methylation of key genes in bronchial epithelial cells.  The work should help provide a better understanding of how air pollution contributes to chronic airway inflammation in asthma, and to establish a role for DNA methylation changes as a mechanism by which this occurs. It should also serve as the basis for future collaborations, bridging the clinical and basic science research strengths between the partner institutions, allowing greater determination of the factors that contribute to uncontrolled moderate-to-severe asthma and the epigenetic mechanisms that regulate various facets of asthma pathogenesis.

Outcomes

• 50 patients with moderate-to-severe asthma were recruited at PKUHSC with samples collected.
• DNA from both whole blood and isolated T cells have been transported from PKUHSC to Michigan Medicine for analyses.
• 1 PhD student from PKUHSC had a 4-month training at Michigan Medicine.
• 2 abstracts were presented at the American Thoracic Society in 2017 and 2018.

Publications

1. Tripathi P, Deng F, Scruggs AM, Chen Y, Huang SK. Variation in doses and duration of particulate matter exposure in bronchial epithelial cells results in upregulation of different genes associated with airway disorders. Toxicol In Vitro. 2018 Sep;51:95-105. PMID: 297530511.

Margaret Gyetko, MD
Professor of Internal Medicine (Emeritus)
University of Michigan Medical School
[email protected]

Bei He, MD
贺蓓教授
Professor of Pulmonary Medicine
Director of Respiratory Diseases Center
Peking University Third Hospital
[email protected]

JI Program: Pulmonary

Status: Completed

Summary

Chronic obstructive pulmonary disease (COPD) is a progressive and potentially fatal lung disease, and is a leading cause of death in both the U.S. and China. COPD is most commonly caused by direct smoke exposure and indoor air pollution caused by combustion of biomass fuels. There is currently no curative treatment for COPD. This research aims at determining the respiratory microbiome in healthy non-smokers, “healthy” smokers, and smokers with COPD at various stages, and to determine if a particular microbiome signature is associated with COPD. Data will be collected at both Michigan Medicine and PKUSHC to compare populations. Many factors that are thought to affect the pulmonary microbiome, such as smoking history, BMI, diet, antibiotic use, and use of biomass fuels in cooking

Outcomes

• 3 PKUHSC faculty members received extensive training at Michigan Medicine mentored by Dr. Gyetko.
• 1 UMMS resident completed a one-month clinical rotation at PKUHSC mentored by Dr. He.
• Awarded $600,000 from United Health Group & NHLBI Collaborating Centers.
• Completed a multi-national project that included PKU and U-M.

Publications

1. Erb-Downward JR, Sadighi Akha AA,…Bei He, ... Huffnagle GB. (2012) Use of direct gradient analysis to uncover biological hypotheses in 16s survey data and beyond. Sci Rep. 2012; 2: 774.