After decades of research efforts and billions of dollars in cost, diabetes and obesity still stand as major health challenges in the developed and developing worlds. The elusive nature of the metabolic disorders stems largely from incomplete understanding of the growth factor signaling pathways that regulate cellular homeostasis in different metabolic cell types. Two long-standing questions include: 1) How do cell membrane bound receptors directly mediate their effects on gene expression in the nucleus thereby regulating a cell's response to a metabolic challenge and 2) Whether insulin receptor (IR) and insulin-like growth factor-1 receptors (IGF1R) that activate common downstream proteins in their signaling pathways, have specific and distinct gene targets that would be suitable for novel drug targets for each receptor. Our work presents the novel evidence that IR and IGF1R, classic cell membrane bound receptors, show ligand-dependent translocation to the nucleus of mouse and human cells. Our genome-wide chromatin immunoprecipitation (ChIP) sequencing analyses provides compelling evidence for the direct recruitment of IR and IGF1R to genomic sites, unfolding a novel paradigm that has the potential to address critical scientific questions imperative to therapeutic innovation, that have remained largely unexplored. We believe our findings have the exciting potential to: a) better understand how signals initiated at the cell membrane are translated into a response to regulate gene expression in the nucleus, b) delineate the differences in IR and IGF1R actions and their response to growth factor stimuli to regulate metabolic function, and c) identify novel players and mechanisms of growth factor signaling that impact both the genetic and epigenetic mechanisms across several metabolic tissues, and hence have broad implications for the treatment of metabolic diseases and cancer.
We propose to continue to focus on investigating the roles of the insulin and IGF-1 receptors in regulating islet biology. Specifically we will examine how the cell membrane receptors shuttle to the nucleus in mammalian cells to impact epigenetic and genetic mechanisms. This approach will likely yield novel insights into the regulation of metabolic cells with the possibility of identifying new therapeutic targets to counter metabolic diseases and cancer.
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