Date of Completion

5-8-2020

Embargo Period

5-8-2020

Keywords

TRP Channels, TRP, TRPM7, TRPM2, ion channels, PIP2, cardiovascular disease, heart disease, heart failure, atherosclerosis, oxidative stress

Major Advisor

Dr. Lixia Yue

Associate Advisor

Dr. Kevin Claffey

Associate Advisor

Dr. Kimberly Dodge-Kafka

Associate Advisor

Dr. Linda Shapiro

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Transient receptor potential (TRP) channels are evolutionarily conserved ion channels that have been implicated in a wide range of physiological and pathophysiological responses. As versatile ion channels that are permeable to calcium, the exact nature of these ion channels have been furiously studied since its initial discovery in Drosophila. Many TRP channels are thought to be gated by PIP2, a well-known membrane signaling molecule. Here we show that membrane potential alters PIP2 in such a way to reduce TRPM7 activity, presumably through PIP2 depletion. This novel mechanism of TRPM7 regulation gives us a clearer picture into a complicated protein that has been implicated in processes ranging from embryonic development to cancer. Furthermore, we show how TRP channels are involved in the development and progression of various cardiovascular diseases. Our research implicates the oxidative stress activated channel TRPM2 in the progression of atherosclerosis, with data pointing to its role in driving inflammation by increasing circulating myeloid cell populations. We also show that the bifunctional channel-enzyme TRPM7 plays a deleterious role in the cardiac fibrogenesis cascade in hypertensive heart failure, and deletion of Trpm7 specifically in the cardiac fibroblast is protective against negative cardiac remodeling. My research demonstrates not only how TRP channels are important mediators of cardiovascular disease, but also how they are regulated at a basic molecular level.

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