This proposal describes a 5-year training program for developing an academic career in medicine and endocrinology. The principal investigator has completed his fellowship training in endocrinology at UCSD, and now will expand his scientific skills by pursuing postdoctoral training in Dr. Ronald M. Evans laboratory at the Salk Institute. This proposal focuses on biochemical, molecular and cellular aspects of atherogenesis, especially as it relates to signaling by nuclear hormone receptors, PPAR?, PPAR? and LXRs. We have previously identified the scavenger receptor CD36, LXR? and the reverse cholesterol transporter ABCA1 as either direct or indirect PPAR? target genes. Through these target genes PPAR? has the potential to both promote (CD36) and inhibit (LXR?/ABCA1) atherogenesis. The goal of Specific Aim 1 is to investigate whether the anti-atherogenic effects of TZDs are dependent upon PPAR? expression in lesion macrophages. Currently, it is simply unknown whether the TZDs principle action is in peripheral tissues or the lesion. Additional studies outlined in Specific Aim 2 will determine whether the LXR regulated cholesterol efflux pathway is critical to the anti-atherogenic actions of TZDs.
In Specific Aim 3, we will use PPAR? null ES cells to unequivocally establish the role of this receptor in macrophage lipid metabolism and atherosclerosis. Transplantation of bone marrow from genetically engineered mice into LDLR -/- mice will allow us to specifically evaluate the role of these receptors in macrophages and atherosclerosis. This will be performed in collaboration with Dr. Linda K. Curtiss of the Scripps Research Institute, a pioneer in the field of bone marrow transplantation and atherosclerosis. Collectively, these studies will provide insights into the transcriptional control of atherogenesis, and potentially lead to the identification of new therapeutic targets to treat this chronic disease. Dr. Evans' laboratory at the Salk Institute, Dr. Curtiss's laboratory at the Scripps Research Institute and UCSD provide an ideal setting for my training as a physician-scientist. This setting combines the strengths of both basic science and clinical research in nuclear receptors and vascular disease, and thus will be an extremely fertile environment for my development as a principal investigator.
