Student Presentation -- Azmi Ahmad
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Ph.D. Research Proposal, Thursday August 17, 2017 -- Investigating the role of TRPC1 and TRPC6 channels in cardiac hypertrophy

CVRTI Room 152, 1:00 pm

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Speaker: Azmi Ahmad. Advisor: Dr. Frank Sachse


Abstract:

Transient receptor potential canonical (TRPC) ion channels are abundantly expressed in the mammalian heart, and thought to play a role in mechano-electric coupling in cardiomyocytes. TRPC channels constitute a family of seven calcium permeable ion channels, named TRPC1 to 7. Studies on TRPC1 and TRPC6 suggested a crucial role of these channels in cardiac hypertrophy, yet the physiological role of TRPC1 and TRPC6 in cardiac cells remains ill defined. Proposed roles of TRPC channels in cardiomyocytes include both receptor- and store-operated-calcium-entry (ROCE and SOCE, respectively). Suggested sites of TRPC1 and TRPC6 in cardiomyocytes include sarcolemma, tubular-system, intercalated discs and mitochondria. A recent study on skeletal myocytes proposed TRPC1 to localize in the sarcoplasmic reticulum (SR) membrane.

Our preliminary studies on rabbit ventricular myocytes indicate that TRPC1 and TRPC6 preferentially colocalize with intracellular membranes, in particular the SR, and act as calcium leak channels modulating SR-calcium load. Here, I propose to test the hypothesis that TRPC1 and TRPC6 channels reside in the membrane of the SR and act as calcium leak channels to modulate cytosolic calcium concentration. I will use a unique adenoviral tool to explore the role of TRPC1 and TRPC6 in neonatal rat ventricular myocytes (NRVMs). In aim 1, I will investigate TRPC1 localization and contribution to calcium signaling in NRVMs. In aim 2, I will examine the location and contribution of TRPC6 in NRVMs. In aim 3, I will explore changes in TRPC1 and TRPC6 localization and expression in a rabbit model of hypertrophy using an established transverse aortic constriction (TAC) model. The proposed studies will set the stage for investigations on molecular pathways involving TRPC1 and TRPC6 to be used as possible pharmacological treatment of cardiac hypertrophy.