Research in Prasanna's laboratory is supported through funds from National Institutes of Health (NIH-R01) and American Heart Association (AHA).

Our Research Mission
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Overall research focus in my laboratory is to study mechanisms of cardiovascular diseases and develop novel therapeutic strategies to enhance stem cell differentiation and function and promote cardiac regeneration and repair. Current scientific work in our laboratory involves two broad areas of research. I) To understand the molecular mechanisms by which diabetes increases the risk for coronary artery disease and the resulting pathophysiological consequences. II) to define factors that affect cardiovascular regeneration in diabetes, in addition to exploring newer and ideal stem cells and biomaterials for therapeutics after cardiac ischemic injury. 

Over the years, our laboratory has developed a strong scientific background and expertise in cardiovascular pathophysiology, molecular and cellular signaling mechanisms and extensive hands-on experience and understanding of mouse surgical models of heart failure (MI, TAC) and bone marrow transplantation systems. Our approach involves use of pharmacological, biochemical, molecular, cellular and physiological techniques including transgenic mice and relevant surgical models to address fundamental questions about the mechanisms of cardiovascular disease progression in diabetes, and to develop potential therapeutic approaches to intervene the diseases.

It is our hope and expectation that these studies will identify new targets that will aid in development of future drugs and new therapies for prevention and
treatment of cardiovascular disease complications in diabetes.
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Novel strategies for cardiovascular regeneration and repair

Acute ischemic injury and chronic cardiomyopathies lead to permanent loss of cardiac tissue. Transplantation of bonemarrow (BM)-derived progenitor cells has the potential to improve cardiac function after ischemic injury. However, number and functional capacity of these cells are impaired in diabetes. Our objectives are to determine the impact of the diabetic milieu (high glucose and fatty acids) on progenitor cell biology and function and their contribution to myocardial repair in response to ischemic injury.

Ongoing Projects:
1. microRNA mediation of Endothelial Progenitor Cell function and therapy for Myocardial Ischemia.
2. Paracrine regulation of cellular biology and function under cardiac stress conditions.
3. Clearance of apoptotic cardiac cells (efferocytosis) for inflammation resolution and efficient cardiac repair.
4. Use of Nano- and biomaterials to modulate cardiac pathology and regeneration.
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3D culture3D scaffolds for disease modeling and tissue repair

Stem cell/macrophage dysfunction has been associated with development of diabetic complications (nephropathy, atherosclerosis, neuropathy, foot ulcers and retinopathy). Cellular biology and function is influenced by tissue microenvironment.

Our goal is to use 3D culture and/or scaffolds to study the interaction of tissue microenvironment with macrophage/stem cells. We will use 3D scaffolds-
-to evaluate the influence of this interaction on cellular function,
-disease modeling and
-in vivo repair of injured tissues. 


Opportunity are available for Master’s student with interest in research thesis.

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Cardiovascular Pathophysiology in Diabetes
Patients with diabetes and obesity have increased risk for cardiovascular disease. These metabolic conditions are associated with chronic inflammation, oxidative stress, and insulin resistance leading to severe coronary events and worse clinical outcomes. The long-term goal of our research is to determine mechanisms by which diabetes/obesity increase risk for coronary artery disease and the resulting pathophysiological consequences. In this context, macrophages (part of the innate immune system) have emerged as a key pathogenic link between diabetes/obesity and the resulting coronary artery disease. Macrophages play critical role in regulating the body's inflammatory response to environmental stimuli, pathogen recognition, clearing cellular debris and inflammatory cytokine secretion. However, their chronic activation in diabetes/obesity might induce endothelial dysfunction, cardiac cell death, extracellular matrix remodeling and contractile dysfunction leading to heart failure. Our research efforts are focused on understanding the cellular and molecular connections between macrophage biology, chronic inflammation, oxidative stress and insulin resistance, and diabetes/obesity-induced cardiovascular disease. These studies will facilitate development of novel therapies that specifically target recruited macrophages to treat the underlying inflammation and insulin resistance in patients with type 2 diabetes/obesity. 

Ongoing Projects:

1. Role of macrophage in cardiac pathophysiology in experimental diabetes.  
2. Mechanisms of cardiomyocyte pyroptosis.
3. Application of bioengineering tools to enhance wound healing in diabetes.
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 mir377 summaryStem cells, cardiovascular regeneration and repair

Acute ischemic injury and chronic cardiomyopathies lead to permanent loss of cardiac tissue. Transplantation of bonemarrow (BM)-derived progenitor cells has the potential to improve cardiac function after ischemic injury. However, number and functional capacity of these cells are impaired in diabetes. Our objectives are to determine the impact of the diabetic milieu (high glucose and fatty acids) on progenitor cell biology and function and their contribution to myocardial repair in response to ischemic injury.

Our on-going studies to investigate the effect of heart failure (HF) on microRNA dysregulation and human CD34+ cells (currently in clinical trials) has yielded valuable scientific information. Human cardiac biopsies from patients with HF showed significant increases in miR-377 expression compared with nonfailing control hearts. In vitro over-expression of miR-377 in hCD34+cells significantly diminished their ability to form vascular tubes and secrete proangiogenic proteins. Most importantly, in a mouse model of myocardial ischemia-reperfusion, transplantation of miR-377 knockdown hCD34+cells into ischemic myocardium promoted their angiogenic ability, attenuating cardiac fibrosis and improved left ventricular function.
Work published in Journal of the American College of Cardiology, 66(20), 17–24 November 2015, Pages 2214–2226

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Diabetes impairs phagocytosis of dead cellmir126 summary
Patients with diabetes and obesity have increased risk for cardiovascular disease. Efferocytosis, a process of removal of dead cells by phagocytosis (like macrophages) after physiological and/or pathological apoptotic cell death, is crucial for tissue homeostasis. Aberrant clearance leads to progression of a number of human chronic inflammatory diseases such as autoimmune and neurological disorders, inflammatory lung diseases or atherosclerosis. We are studying the influence of diabetes on macrophage dysfunction and clearance of dead cells and its implications on heart disease. We recently discovered that diabetes has a negative influence on this fundamental cellular process.
Read more about this discovery

In summary, we show that diabetes-induced decrease in miR-126 expression results in upregulation of ADAM9 expression that in-turn leads to proteolytic cleavage of MerTK and formation of inactive sMer. The resulting decrease in MerTK phosphorylation (inactivation) leads to reduced downstream cytoskeletal signaling required for engulfment and thus decreases efferocytosis of apoptotic cells and lower inflammation resolution, which eventually results in defective organ repair. This is termed as “not ready to eat” signal of macrophages in the diabetic conditions. Image on the right depicts that overexpression of miR-126 suppresses ADAM9 expression, which in turn rescues efferocytosis in diabetic conditions. This sends “ready to eat signal” from the miR-126 overexpressed macrophages in diabetic conditions. This eventually results in improved organ repair and regeneration. 
Published in Scientific Reports, 2016 (6); Article number: 36207