Dysfunctional insulin signaling is a major contributor to the development of type 2 diabetes, a metabolic disease afflicting 350 million people worldwide. Type 2 diabetes is characterized by increased blood glucose levels, the consequence of insulin resistance and deficient insulin production. TOR complex 2 is a highly conserved pathway that functions critical to the cellular response to insulin. Mice lacking functional target of rapamycin (TOR) complex 2 in liver fail to respond to insulin, developing hallmarks of diabetes including uncontrolled hepatic glucose output. Although the AGC family kinases such as Akt, serum and glucocorticoid-induced kinase (Sgk) and protein kinase C (PKC) serve as downstream outputs of TOR complex 2, a major gap in the knowledge is in what genes lie further downstream of this signaling system. The proposed work expands upon our novel findings that TOR complex 2 lies upstream of epigenetic machinery thought to function specifically on repression of X chromosomal genes in C. elegans. Our previous studies show that TOR complex 2 lies genetically upstream of histone H4 lysine 20 methyltransferases, SET-1 and SET-4, to modulate metabolic and developmental processes. We hypothesize that the TOR complex 2 nutrient responsive pathway regulates histone modifiers to modulate chromatin condensation state and global gene expression in order to control metabolism, development and reproduction in C. elegans. We will address our hypothesis by 1) determining the site and mechanism of action of these epigenetic modifiers which function downstream of TOR complex 2 and 2) by identifying gene expression changes that are modulated by the chromatin state under the control of TOR complex 2. The proposed research is innovative as it uses the powerful genetics of C. elegans to probe global TOR complex 2 biology, which is lethal when globally mutated in mammalian systems. The results from this work will provide new genetic targets previously overlooked by other model systems and offer insight into the role epigenetics plays in type 2 diabetes. The proposed research will expand my training in molecular genetics and metabolism and provide a strong skillset for advancement into an independent research career.

Public Health Relevance

Type 2 diabetes is a devastating metabolic disorder affecting millions of individuals worldwide. Despite advancements in diagnosis and treatment, the full spectrums of factors that make certain individuals more prone to diabetes are not understood. In the proposed project we will explore how a key signaling system deranged in type 2 diabetes contributes to the disease by changing gene expression.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1)
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Castle, Arthur
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Massachusetts General Hospital
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Webster, Christopher M; Pino, Elizabeth C; Carr, Christopher E et al. (2017) Genome-wide RNAi Screen for Fat Regulatory Genes in C. elegans Identifies a Proteostasis-AMPK Axis Critical for Starvation Survival. Cell Rep 20:627-640