The M-BoCA program is made up of various research labs that share a common ground of Cardiovascular Aging research.
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 Goldstein Lab projects are focused on how aging impacts inflammation during acute viral infections and during chronic inflammatory disorders such as atherosclerosis.
The Goldstein Lab is interested in how aging impacts immunity. Previously they challenged the paradigm that declining immune function is responsible for age-associated disorders. In murine viral infection models, theydetermined that exaggerated IL-17 production by NKT cells induces lethal immune pathology (Cell Host and Microbe, 2009). In murine vascular models, they demonstrated that elevated inflammatory responses by vascular smooth muscle cells may predispose to atherosclerosis (ATVB, 2012). Recently, they demonstrated that changes within the vasculature may underlie how aging enhances atherosclerosis (Aging Cell, 2016). Finally, in murine transplant models they documented that enhanced responses by naïve CD8+ T cells may impair immune tolerance with aging (JI, 2011). In sum, they have made innovative findings, challenging current paradigms, that elevated immune responses explain age-associated phenotypes.
The Greve Lab focuses on optimizing or developing preclinical imaging techniques (primarily MRI) to study vascular biology in a number of organ systems, in health and disease, using preclinical models of the human condition. Where appropriate, The Greve Lab collaborates with experts in computational fluid dynamics modeling, to complement experimental data. Primary biological questions of interest related to vascular biology concentrate on the cardiovascular and central nervous systems.
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 Kanthi laboratory studies the biology of venous diseases, including deep vein thrombosis (DVT), which occurs when potentially fatal blood clots develop in the deep veins of the legs and arms; and vascular bypass graft failure, which occurs when veins are used as bypass grafts to restore blood flow to tissue around arterial blockages.
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.
Aging is a conserved but poorly understood biological phenomenon. In invertebrates, overexpression or hyperactivity of sirtuins – homologs of the yeast Sir2 deacetylase – confer extended lifespan. Mammals possess seven sirtuins, called SIRT1-SIRT7. Many of these proteins modulate metabolic processes; their potential roles in regulating aging in mammals are uncharacterized. The Lombard Group previously showed that SIRT3 is a mitochondrial factor that deacetylates numerous protein targets in this organelle; they are currently elucidating the biological significance of this activity. More recently they have found that calorie restriction (CR), an intervention that extends lifespan in many organisms, is also associated with perturbations in mitochondrial acetylation. The Lombard Group is currently working to understand the impact of CR-related acetylation changes on one key substrate identified in these studies, the pyruvate dehydrogenase complex (PDC). PDC governs metabolic flux into the Krebs cycle and is the major regulator of glucose utilization in mammals.
With respect to non-mitochondrial sirtuins, The Lombard Group previously showed that SIRT6 is a nuclear protein that suppresses genomic instability and enhances genotoxin resistance in cells. SIRT6-deficient mice die of a degenerative disorder characterized by profound metabolic abnormalities. The Lombard Group is working to understand the basis for this phenotype through cell culture studies as well as analysis of conditional knockouts and overexpressing mouse models.
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.
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 Sutton lab is drawn to the fascinating interplay of hemodynamics and the biology of vascular aging. There is a great need to make strides to better treat the burgeoning population of older patients with vascular disease. Our goal is to improve the health of older adults with cardiovascular disease by contributing new information to the field, which will lead to safer and more effective treatments. Currently, most medical treatments for cardiovascular disease focus on preventing atherosclerotic plaque progression or clot formation. Many of these life-saving treatments are administered at the cost of side-effects with significant morbidity, e.g. bleeding. We are studying how modulation of ectonucleotidases such as CD39 and CD73 influence vascular aging, leading to changes in vessel wall stiffness, calcification, and morphology. We hope to contribute fundamental insights into the molecular underpinnings of vascular aging.
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: (1.) use a systems approach to construct and test new hypotheses on cause-and-effect relationships in the etiology of hypertension and hypertensive heart disease; (2.) 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; and (3.) use systems modeling to improve diagnosis and realize applications in precision medicine for cardiovascular disease.