Atherosclerosis is a chronic inflammatory disease involving a complex interplay between resident vascular wall cells and infiltrating immune cells. Loss of T cell homeostasis contributes to both plaque development and inflammation. Regulatory T cells (Tregs) inhibit atherosclerotic development and progression through suppression of immune responses, including the actions of pro-inflammatory T helper 17 (Th17) cells. We identified the expression of the nuclear receptors PPARy and REVERBa/B in thoracic periaortic Tregs and Th17 cells, respectively. Our underlying hypothesis is that the development of the atherogenic lesion is driven by a pro-inflammatory gene network that can be modulated at the transcriptional level by PPARy and REVERBa/B. Our approach is to employ complementary loss-of-function and drug? mediated gain-of-function mouse studies, as well as genome-wide transcriptomic and cistromic studies, to define the molecular mechanisms of PPARy and REVERBs actions in atherogenesis.
In Aim 1, we will employ a novel Treg-specific PPARy knockout mouse in combination with PPARy agonists, to understand the role of PPARy-dependent signaling in visceral adipose tissue-resident Tregs during the development of atherosclerosis.
In Aim 2 we will determine PPARy's genome-wide chromatin binding sites, define the PPARy-dependent transcriptome, and map the translatome (Ribo-seq) of peri-aortic fat Tregs in order to determine the signaling pathways and molecular mechanisms of PPARy action in Tregs.
In Aim 3 we will examine the role of REVERBa/B in attenuating pro-Inflammatory Th17 cells in the context of atherogenesis. These REVERBs naturally oppose RORy, the Th17 lineage specifier. Our approach is to utilize mice with selective deletion of both REVERBa and REVERBB in T cells, in combination with the biologically-available REVERB agonist, SR9009, to determine the consequences of REVERB signaling on the differentiation of Th17 cells and the resultant effects on the initiation and progression of atherosclerosis. Similarly, in Aim 4 we will identify direct and indirect target genes of REVERBa and REVERBB by comparing their genome? wide chromatin binding sites to the REVERB-dependent transcriptomes in Th17 cells, thereby shedding light on the mechanisms of REVERB-mediated repression. These highly integrated Aims employ biochemical, molecular, genetic, pharmacologic and physiologic approaches to clarify the competing roles of the immuno? suppressive Tregs and the pro-inflammatory Th17 cells in this disease. Characterization of the roles of these therapeutically-accessible nuclear receptors in these immune cell populations may lead to the development of novel small molecule drugs for the prevention and treatment of atherosclerosis.
This proposal is directed at identifying how nuclear receptors regulate the adaptive immune response integral to the development and progression of atherosclerosis. Insights gained from this work into the receptor-regulated pathways may lead to the development of new diagnostics and therapeutics for cardiovascular disease, the leading cause of death in the Western world.
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