The long-term goal of our research is to understand the mechanisms by which ion channel-mediated calcium influx regulates cellular physiology. Currently, we focus on the role of TRP (transient receptor potential) channels, a superfamily of cation channels that are conserved from worms to humans and have been implicated in a number of human diseases. Our current understanding of the function and regulation of TRP channels primarily derives from in vitro studies performed in various cell culture systems; however, the roles of these channels in regulating cellular physiology in vivo, particularly in the context of whole organisms, have not been well evaluated. Here we propose to characterize the in vivo function and regulation of TRP channels in C. elegans, a genetically tractable model organism whose genome encodes all the seven TRP subfamilies, all of which are highly homologous to their vertebrate counterparts. We will focus on two groups of calcium-permeable TRP channels, TRPC and TRPN. As a first step, we have isolated genetic mutants of all the members in these two TRP subfamilies. We will characterize the defects of these trp mutants, and design a series of experiments aimed at elucidating the mechanisms by which these TRP channels regulate calcium signaling at the cellular and organismal level. We will also test some hypotheses with respect to the role of these TRP channels in regulating general calcium signaling. To do so, we will apply a multidisciplinary approach involving molecular genetics, cell biology, cellular imaging, electrophysiology and biochemistry. Given the high conservation of TRP family channels throughout phylogeny and the fact that mutations in TRP family channels lead to a number of human diseases such as polycystic kidney disease, familial focal segmental glomerulosclerosis and hypomagnesemia, the proposed studies may provide novel insights into our understanding of the role of TRP family channels in cellular physiology and disease. ? ? ?
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