Cells respond to their environment by detecting extracellular signals that dictate how energy resources, including lipids, are utilized. In complex tissues, cells with specialized metabolic functions perceive developmental, nutritional, and environmental inputs that strictly control the allocation of lipids into different metabolic pathways in order to maintain organismal energy homeostasis. Dysregulation of these pathways can lead to metabolic disease and cancer. The molecular mechanisms that govern lipid homeostasis, including the intercellular signals and the intracellular regulatory factors that control metabolic flux, remain poorly understood. Proliferative signal transduction pathways, including mTOR and MAP Kinase, promote cellular growth and influence metabolic function; however, the upstream regulators and downstream effectors of these pathways that control lipid homeostasis remain largely unknown. The long-term scope of this research program is to uncover new regulatory factors of pro-growth signal transduction pathways and to elucidate the molecular mechanisms by which they exert metabolic control. We will employ an interdisciplinary approach, using unbiased genetic strategies in combination with functional genomics and biochemical analyses in different biological systems, to address several fundamental questions in the field of lipid homeostasis. Although mTOR and MAP Kinases are known to participate extensively in metabolic and growth control, major gaps exist in our understanding of how these pathways influence lipid allocation. The first goal of this project is to identify the inter-tissue signaling events that regulate the activity of mTOR Complex 2 (mTORC2), which is poorly understood in any system, and to further define the metabolic function of mTORC2 in a specialized cell type - the C. elegans intestine. Leveraging the power of unbiased genetic and genomic approaches in the worm, we will then identify the transcriptional effectors of mTORC2 signaling that are responsible for controlling the expression of metabolic genes in order to gain a comprehensive view of how mTORC2 regulates energy homeostasis. MAP Kinases, which function broadly in stress responses and cell proliferation, are crucial for maintaining cellular homeostasis; however, how MAPK signaling controls lipid metabolism pathways is poorly understood. The second goal of this project is to define how different MAPK pathways influence lipid homeostasis, then investigate the potential avenues of cross-talk between MAPK and other pro-growth pathways, and finally to employ an unbiased genetic approach to identify the downstream effectors of MAPK signaling that control lipid homeostasis and growth. Together, this research will shed light on how proliferative signaling pathways act together to shape the metabolic function of specialized cells and provide mechanistic insight into how dysregulation of these pathways can lead to metabolic dysfunction and disease.
Cells respond to their surroundings by perceiving extracellular signals, which trigger intracellular signaling events that shape how energy resources, including lipids, are allocated between fundamental cellular processes. The goal of this project is to elucidate the molecular mechanisms by which pro-growth signaling remodels lipid metabolism pathways to maintain organismal energy homeostasis. This work will identify new proteins and signaling networks that participate in metabolic regulation, as well as yield mechanistic insight into the underlying causes of a wide range of human metabolic diseases and cancers.
