Dr Ashish Misra

BSc, MTech, PhD
"Research is a marathon, not a sprint. You have to work through the ups and downs."
Dr Christina Bursill completed her PhD in lipid metabolism at the University of Adelaide before doing postdoctoral work at Oxford University at the Wellcome Trust Centre of Human Genetics. She returned to Australia in 2007 to take up a position at the HRI with Professors Kerry-Anne Rye and Philip Barter as part of the Lipid Research Group. In 2008, Dr Bursill was awarded a prestigious National Heart Foundation of Australia Career Development Fellowship. In 2010, she formed the Immunobiology Group at the HRI.

Dr Ashish Misra received his Master’s degree from the Indian Institute of Technology, Kanpur, India, and his PhD in cell and molecular biology from Nanyang Technological University, Singapore in 2011. Dr Misra joins HRI from Yale Cardiovascular Research Center (YCVRC), Yale University where he was a Postdoctoral Associate. He is a recipient of the prestigious Yale Brown-Cox Postdoctoral Fellowship. His research focuses on blood vessel wall development and the pathogenesis of diverse cardiovascular diseases. His recent work demonstrated the molecular processes and signals that are required for blood vessel wall patterning and how aberrant molecular signalling leads to vascular abnormalities. 

Current Appointments

Atherosclerosis and Vascular Remodeling Unit Leader

Heart Research Institute

Dr Ashish Misra leads group:
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More about Dr Ashish Misra

Research Project Opportunities
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The role of Notch signalling in cardiovascular disease and related pathologies.

Notch has been comprehensively studied as a conciliator of cell-to-cell communication that mediates cell fate decisions of progenitors. While Notch signalling has been extensively studied in cell fate determination at distinct development stages of mammalian cells as well as cancer stem cell progenitor maintenance and renewal, the functional role of Notch signalling in vascular wall patterning and cardiovascular disease is not well understood. By using advanced microscopic techniques, fate mapping approaches and single cell clonal analysis, we aim to study the role of Notch signalling in blood vessel wall patterning and maintenance of smooth muscle cell progenitors in developing walls as well as disease of the vasculatures. Thus, we believe that the investigation of Notch signalling in vascular biology promises to be a very fruitful way forward to designing new therapeutics.

Factors and regulators of smooth muscle cells and macrophages in progression of atherosclerosis.

Atherosclerosis is a leading cause of death worldwide. Atherosclerotic plaque or atheroma consist of smooth muscle cells (SMCs) and macrophages in the malefactor lesion and are comprised of a lipid-laden core covered by a fibrous cap. Plaque rapture leads to thrombosis with dire consequences, such as myocardial infarction and stroke. SMCs and macrophages are key players in atherogenesis. Although extensive research has been done in the past on atherosclerosis, exactly how cells from normal blood vessel walls contribute to atherosclerotic plaques is still far from clear. Our studies aim to discover the origin of the cells that make normal blood vessels and how these cells contribute to atherogenesis. Recently, our studies established that very few SMCs have the potential to migrate and proliferate from the blood vessels and produce most of the SMCs in atherosclerotic plaques. The focus of our current studies is to identify new signalling molecules, factors and/or pharmacological inhibitors that can modulate SMC phenotypic switching and macrophage infiltration into the plaque to change the plaque composition and thereby promote plaque stability.

Featured Publication
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Integrin beta3 regulates clonality and fate of smooth muscle-derived atherosclerotic plaque cells. Nat Commun. 2018 May 25;9(1):2073. doi: 10.1038/s41467-018-04447-7

Smooth muscle cells (SMCs) play a key role in atherogenesis. However, mechanisms regulating the expansion and fate of pre-existing SMCs in atherosclerotic plaques remain poorly defined. Here we show that multiple SMC progenitors mix to form the aorta during development. In contrast, during atherogenesis, a single SMC gives rise to the smooth muscle-derived cells that initially coat the cap of atherosclerotic plaques. Subsequently, highly proliferative cap cells invade the plaque core, comprising the majority of plaque cells. Reduction of integrin β3 (Itgb3) levels in SMCs induces toll-like receptor 4 expression and thereby enhances Cd36 levels and cholesterol-induced transdifferentiation to a macrophage-like phenotype. Global Itgb3 deletion or transplantation of Itgb3(-/-) bone marrow results in recruitment of multiple pre-existing SMCs into plaques. Conditioned medium from Itgb3-silenced macrophages enhances SMC proliferation and migration. Together, our results suggest SMC contribution to atherogenesis is regulated by integrin β3-mediated pathways in both SMCs and bone marrow-derived cells.

Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosis. J Exp Med. 2016 Mar 7;213(3):451-63. doi: 10.

The aorta is the largest artery in the body, yet processes underlying aortic pathology are poorly understood. The arterial media consists of circumferential layers of elastic lamellae and smooth muscle cells (SMCs), and many arterial diseases are characterized by defective lamellae and excess SMCs; however, a mechanism linking these pathological features is lacking. In this study, we use lineage and genetic analysis, pharmacological inhibition, explant cultures, and induced pluripotent stem cells (iPSCs) to investigate supravalvular aortic stenosis (SVAS) patients and/or elastin mutant mice that model SVAS. These experiments demonstrate that multiple preexisting SMCs give rise to excess aortic SMCs in elastin mutants, and these SMCs are hyperproliferative and dedifferentiated. In addition, SVAS iPSC-derived SMCs and the aortic media of elastin mutant mice and SVAS patients have enhanced integrin β3 levels, activation, and downstream signaling, resulting in SMC misalignment and hyperproliferation. Reduced β3 gene dosage in elastin-null mice mitigates pathological aortic muscularization, SMC misorientation, and lumen loss and extends survival, which is unprecedented. Finally, pharmacological β3 inhibition in elastin mutant mice and explants attenuates aortic hypermuscularization and stenosis. Thus, integrin β3–mediated signaling in SMCs links elastin deficiency and pathological stenosis, and inhibiting this pathway is an attractive therapeutic strategy for SVAS.

2017 Postdoctoral Associate, Yale Cardiovascular Research Center (YCVRC), Yale University, USA

2011 PhD in cell and molecular biology, Nanyang Technological Institute(NTU), Singapore

2005 MTech, Indian Institute of Technology (IIT/Kanpur), India

Awards for research
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2017–2022 Sydney Cardiovascular Fellowship, Charles Perkins Centre of the University of Sydney and Heart Research Institute

2013–2014 James Hudson Brown - Alexander Brown Coxe Postdoctoral Fellowship, Yale School of Medicine