Regulation of Channel Enzymes and Their Contribution to Cardiac Fibrosis

Date of Completion

January 2011

Keywords

Biology, Cell

Degree

Ph.D.

Abstract

Given the unique characteristic of "channel enzymes" and the potential critical role of TRP channels in the cardiac fibrosis calcium signaling, the main focus of this thesis is to investigate the biophysical properties of the channel enzymes (Chapter II), and determine how TRP channels are regulated during fibrogenesis, and how they contribute to the cardiac fibrosis process (Chapter IV). In the first project (Chapter II) we demonstrated the TRPM2 is negatively regulated by acidified conditions, and calcium alone is capable of activating TRPM2 channel in the absence of ADPR, which was previous thought to be necessary. The second project (Chapter III) focuses on how TRPM6 is regulated by Phosphatidylinositol phosphates (PIPs). We show PIP2 gates TRPM6 channel, PIP2 also contributes to the TRPM6 mediated calcium and magnesium influx. In Chapter IV, we showed the TRPM7 channel is the major calcium permeable channel in cardiac fibroblast, up-regulation of TRPM7 is necessary for the trans-differentiation from fibroblasts to myo-fibroblasts. Recent data from TRPM7 knockout animal suggest that the TRPM7 channel contributes to the pressure over-load induced cardiac hypertension and fibrogenesis. ^ Taken together, my thesis research brought a novel understanding of how channel-enzymes from TRPM subfamily are gated and regulated by their biophysical properties. It explored the physiological role of channel-enzyme in cardiac pathology, also tested the findings more stringently in the knock out animal which produced consistent results and consolidated our findings in the in vivo system. ^

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