# Regulation of lipid homeostasis by proliferative signaling pathways

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $385,143

## Abstract

PROJECT SUMMARY
 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 di...

## Key facts

- **NIH application ID:** 10027645
- **Project number:** 1R35GM137985-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Robert Houston Dowen
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,143
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10027645

## Citation

> US National Institutes of Health, RePORTER application 10027645, Regulation of lipid homeostasis by proliferative signaling pathways (1R35GM137985-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10027645. Licensed CC0.

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