Molecular biological studies of ion channels have revolutionized our perception of the structure and mechanism of action of these physiologically critical. Any comprehensive examination of anion channels in the cardiovascular system must include a goal of identification and characterization of the molecular components underlying these conductances. We have made great strides in recent years towards this goal for cardiac Cl-channels that this project can build on. We have identified I/CLcAMP, I/CLPKC and ICLATP as being encoded by a splice variant of CFTR; we have identified ICLvol as ClC-3 and Icl.ir as ClC-2. Now that several of the molecular components have been identified fundamental questions concerning the genomic expression of these components an be addressed. The working hypotheses for this project is that cardiovascular Cl-channel distribution and modulating is partly determined by genomic influences.
Three specific aims are proposed to address this hypothesis and interface with other projects in the COBRE proposal.
Aim 1 will determine the genomic structure in mouse and human for the established cardiac Cl-channel (CFTR, ClC-2, ClC-3) genetic loci. This information and the genomic clones resulting from the proposed experiments will provide essential tools for several of the other projects in the COBRE proposal.
Aim 2 will determine the molecular distribution of cardiac Cl-channel gene products in cardiac muscles as well as cellular and subcellular localizations.
Aim 3 will establish the molecular identity for the cardiac calcium activated Cl- conductance. While the PI- has been funded for cardiac Cl-channel research, the genomic studies proposed are an entirely new direction for the lab. The COBRE facilities and collaborative projects will allow the PI to utilize novel technologies such as transgenics and genomic approaches to expand his research efforts on the physiological role of cardiovascular Cl-channels.
Showing the most recent 10 out of 77 publications
