M-BoCA Research Partner Labs
Focusing on Cardiovascular Aging
The M-BoCA program is made up of various research labs that share a common ground of Cardiovascular Aging research.
Heart failure affects around 23 million people worldwide each year, however there are currently no curative treatments. The most common cause of heart failure is heart attack during which, an adult heart can lose up to one billion cardiomyocytes. Unlike many other organs in the body, the adult heart cannot regenerate itself and lost cardiomyocytes cannot be replaced. This leads to weakness of the heart muscle, scar formation and eventually patient death.
Following a heart attack, the body's immune system initiates a reparative process to restore the damaged heart muscle. However, if this response persists for an extended period, it can exacerbate heart damage. The precise mechanisms governing the activation and regulation of this immune response remain incompletely elucidated. Intriguingly, there exists a close association between the immune response and the regenerative capacity of the heart. In contrast to higher organisms, more primitive organisms and mammalian neonates possess a remarkable ability to regenerate their heart tissue, which has been attributed to their comparatively rudimentary (immature) immune response to tissue injury. In our laboratory, we employ innovative comparative biology models to further investigate the intricate interactions between immune cells, mature cardiac cells, and stem cells, with the ultimate goal of enhancing cardiac functional recovery following a heart attack.
Our laboratory is dedicated to elucidating the molecular mechanisms underlying heart failure and investigating the intricate involvement of the immune system in this process. To accomplish this, we employ a combination of animal models and clinical studies, which serve as the foundation for our experimental investigations. In particular, our research highlights the critical role played by key components of the immune system, such as neutrophils and macrophages, in both cardiac inflammation and the subsequent recovery phase.
Macrophages, in particular, are indispensable for promoting tissue healing following injury, extending their influence to almost every organ within the body. However, in the context of a heart attack, prolonged pro-inflammatory activation of macrophages can instead contribute to cardiac damage. Therefore, a highly promising strategy to mitigate the initial extent of cardiac injury (preservation) post-heart attack involves modulating the activation state of macrophages, steering them towards an anti-inflammatory phenotype referred to as alternative polarization.
In our laboratory, we pursue diverse approaches aimed at enhancing alternative macrophage polarization. These methodologies encompass not only cell therapy interventions but also the exploration of various novel and repurposed pharmaceutical agents. Through these comprehensive investigations, we aim to expand our understanding of the immune response in cardiac pathology and identify potential therapeutic avenues to improve patient outcomes in the context of heart failure.
The goal of Ailawadi group is to investigate mechanisms surrounding Aortic Aneurysm progression and rupture in both the abdominal and descending aorta with the overall goal being to develop a medical treatment strategy to halt aneurysm progression or prevent rupture.
To that end, the Ailawadi group has several ongoing research projects to investigate inflammation, gender and epigenetics in the context of aortic aneurysms. Recent studies have demonstrated the importance of IL-1 signaling in abdominal (ATVB 2013) and thoracic aortic aneurysm formation (Circulation 2014) and current projects continue to investigate molecular mechanisms of IL-1 signaling in aneurysm rupture.
Separate studies on KLF4 provided the first transgenic evidence supporting the role of smooth muscle cell plasticity behind abdominal aortic aneurysm pathogenesis (Circulation 2013) and projects in the lab continue to investigate epigenetic mechanisms of aortic aneurysm rupture. Finally, the group seeks to develop novel animal models for therapeutic targeting of aortic aneurysms.
The Brody lab is broadly focused on the molecular signals that underlie cardiac disease onset and progression with a specific interest in understanding how intracellular signal transduction in cardiomyocytes is compartmentalized and regionally controlled by lipid modifications to modulate cardiac physiology and pathogenesis.
The laboratory utilizes a combination of mouse genetics, biochemistry, and molecular and chemical biology techniques to gain insight into pathophysiological signaling mechanisms that contribute to human cardiovascular disease.
The Center for Advanced Models for Translational Sciences and Therapeutics (CAMTraST) strives to accelerate the “bench to bedside” process in biomedical research and drug development. Their mission is to develop advanced models for translational sciences and therapeutics as part of the University of Michigan Medical School.
The Cardiology Fellowship research program at the University of Michigan Health System consists of clinical and translational research spanning a variety of topics and interests for cardiology fellows. The program is made up of different private investigators throughout the Health System who offer exceptional expertise in the realm of cardiovascular.
The focus of the UM Cardiovascular Regeneration Core Lab is on cardiovascular cell differentiation of hiPSCs to generate unlimited supplies of patient specific cardiovascular cells for in vitro research. These cells enable patient specific disease modeling in a dish as well as patient specific medication screening for potential cardiotoxicity side effects. These cells and our unique phenotyping platforms can also benefit Drug Discovery projects by providing early stage detection of a compound's effects on human cardiac function in vitro.
The Center for Arrhythmia Research centers around understanding the causes of cardiovascular disease at the molecular, cellular and electrophysiological levels. The specific research objectives are:
- To understand how cells in the heart communicate with each other.
- To understand the mechanism of ventricular fibrillation, the major cause of sudden death.
- To understand the mechanisms of atrial fibrillation, the major cause of stroke.
- To develop new treatments for arrhythmias and prevent sudden death.
- To develop genetic models of heart disease.
- To study the molecular genetics of heart failure.
- To study the molecular causes of diseases of the blood vessels.
The Computational Vascular Biomechanics Lab is driven by its ultimate goal to perform state-of-the-art blood flow simulation. Modeling the cardiovascular system is a challenge that can only be addressed by a deep understanding of physiology, imaging, mathematics, and computation. Their research is focused on the areas of surgical planning, disease research and medical device design and evaluation.
The goal of the Espinoza-Fonseca group is to understand the fundamental molecular motions and interactions that are responsible for regulating calcium transport in cardiac muscle cells, and to design effective molecular therapies to treat human diseases associated with dysregulation of calcium transport in the heart. We approach these multidisciplinary problems with a combination of multiscale computational methods and experimental techniques.
The Holinstat Lab focuses on understanding the complex signaling mechanisms which regulate platelet function, hemostasis and thrombosis. The work in the lab spans four primary areas of platelet research from a basic science and drug discovery program in eicosanoids and lipoxygenases to clinical and translational projects including clinical trials focused on platelet function in type 2 diabetes mellitus, clinical studies on racial disparity in platelet activation and thrombotic risk, identification of novel bioactive lipids in the platelet, and development of first-in-human inhibitors for the prevention of thrombosis and stroke.
The Infection Prevention In Aging Research Group is a collaborative translational research group focusing on reducing infections and antimicrobial resistance in older adults to enhance quality of care, disease outcomes and patient safety. The research group goals are:
- Reduce infections in older adults
- Reduce colonization with multi-drug resistant organisms (MDROs) in older adults
- Define the complex relationship between antimicrobial resistance, healthcare worker contamination, environmental contamination and functional disability in a nursing home (NH) setting
The Isom lab focuses on mechanisms of epileptic encephalopathy and cardiac arrhythmias linked to mutations in voltage-gated sodium channel genes; mechanisms of sudden unexpected death in epilepsy (SUDEP); ion channel structure and function; transgenic mouse models of neurological and cardiac disease; patient-derived induced pluripotent stem cell neurons and cardiac myocytes.
The Lawrence laboratory studies the role of proteases and their inhibitors in health and disease. Primary areas of interest focus on the vascular biology of the CNS (a), and on the development of peripheral vascular and fibrotic disease (b). The principal targets of this work are members of the serine protease inhibitor (serpin) family of proteins, their target proteases, and their downstream protease substrates. A long standing interest has been aimed at understanding how these proteins drive vascular and fibrotic disease processes.
The Lumeng Laboratory performs research that focuses on understanding the negative health effects of obesity. Research in the lab seeks to understand the association between obesity and diseases such as Type 2 diabetes and metabolic syndrome.
The overall goal of the lab is to identify the mechanisms by which inflammation is triggered by obesity in hopes of designing strategies that will break the links between obesity and disease. Efforts in the lab span clinical/translational research, basic cell biology research and the use of animal models of obesity to understand obesity and inflammation.
The Michele laboratory is focused on the molecular mechanisms of human diseases of skeletal and cardiac muscle. By understanding molecular mechanisms of relatively rare genetic disorders, such as human muscular dystrophies, we hope to identify important disease mechanisms and therapeutic targets, and use these findings to understand the pathogenesis of more common idiopathic or acquired forms of skeletal muscle and cardiovascular disease.
The Miller laboratory works on a number of problems related to the genetics of aging in mammals.
Projects underway include:
- Development of methods to slow aging in mice, by diets, drugs, or mutations
- Cellular mechanisms of stress resistance and aging, in mice and in tissue culture
- Comparative biogerontology using cells from species of birds, rodents, and primates
- Gene mapping, biomarkers of aging, and correction of defects in T cell activation
The Mortensen lab is interested in understanding the roles that immune cells have in the pathophysiology of disease. They use a combination of pharmacological and genetic techniques to probe the cellular signaling mechanisms and metabolic effects that regulate immune cells during the disease process. Lab focuses on cardiac disease, stroke, obesity and diabetes.
The Pletcher lab seeks to identify and investigate genetic mechanisms that are likely to be important for aging and age-related disease in humans by focusing on equivalent, conserved processes in the fruit fly, Drosophila melanogaster. Currently they are studying biological pathways involved in sensory perception, neural reward circuits, and reproductive and mating behaviors.
The ScleroLab investigates systemic sclerosis (SSc), a progressive rheumatic disease that damages the skin, lungs, blood vessels, and other organs, and is associated with substantial mortality. The hallmarks of SSc are autoimmunity, vascular damage and dysrepair, metabolic changes, and fibrosis leading to organ failure. Synchronous fibrosis in multiple organs is a defining unique feature of SSc distinguishing it from other rheumatic and autoimmune conditions. Basic and translational research in the ScleroLab is seamlessly integrated with clinical research including observational studies, drug discovery, biomarker identification, and human clinical trials in the Michigan Medicine Scleroderma Program, one of the nation’s preeminent scleroderma programs.
By analyzing tissue biopsies, cells, blood, RNA, and genetic material from SSc patients and healthy controls, we identify molecular changes associated with specific disease phenotypes. We deploy already existing drugs or novel compounds to determine their impact on disease processes in preclinical in vivo and ex vivo models, as well as in early-stage human clinical trials. We partner with a large team of intramural and extramural academic and industry collaborators. The five hallmarks of our research are:
• Disease focus
• Multidisciplinary
• Integration at a systems-level
• Application of advanced discovery technologies
• Rapid translation of findings to the clinic
This comprehensive research pipeline distinguishes our lab and positions the Michigan Medicine Scleroderma Program to be a global leader in advancing the understanding and treatment for this devastating disease.
There are several projects in the Singer lab all focused on gaining an understanding of the long-term impacts of diet-induced obesity on the immune system.
Immune system activation is strongly linked with risk for metabolic and non-metabolic diseases. Hence, gaining a greater understanding of how diet-induced obesity affects the immune system can provide new biomarkers for identifying at risk individuals and novel treatment approaches.
The Virtual Physiological Rat Project is focused on the systems biology of cardiovascular disease—understanding how disease phenotypes apparent at the whole-organism scale emerge from molecular, cellular, tissue, organ, and organ-system interactions.
Ongoing studies are particularly focused on the inexorable link between cardiac and peripheral physiology/pathophysiology in hypertensive heart disease, aiming to understanding how disease phenotypes apparent at the whole-organism scale emerge from molecular, cellular, tissue, organ, and organ-system interactions. Our overall scientific goals are to:
- Use a systems approach to construct and test new hypotheses on cause-and-effect relationships in the etiology of hypertension and hypertensive heart disease
- Discover new strategies for managing, treating, and reversing disease mechanisms and improving/restoring intrinsic cardiac function, neurohumoral control of cardiac function, and physiological blood flow and pressure control.
- Use systems modeling to improve diagnosis and realize applications in precision medicine for cardiovascular disease.
