Genetic and Molecular Mechanisms Connecting Mechanotransduction to Lipid Metabolism

Mechanotransduction and lipid metabolism are fundamental physiological processes essential for maintaining cellular and tissue integrity. Mechanotransduction enables cells to sense and respond to mechanical forces, driving tissue development, homeostasis, and adaptation. Lipid metabolism regulates lipid synthesis, storage, and distribution to maintain energy balance and facilitate cellular signaling. Disruptions in either process can lead to physiological dysfunction and contribute to numerous pathological conditions. Despite their critical biological roles, the molecular and genetic mechanisms that potentially coordinate lipid metabolism and mechanotransduction remain incompletely understood, highlighting the need for further investigation. Our recent findings demonstrate that the mechanosensor PIEZO regulates lipid content and fatty acid-associated prostaglandin synthesis. These findings suggest a potential interplay between mechanotransduction and lipid metabolism, which may function in concert to maintain cellular homeostasis and regulate key physiological processes. This R35 proposal capitalizes on these novel findings linking mechanotransduction and lipid metabolism and outlines two independent yet complementary research directions to address critical knowledge gaps. The first direction focuses on the functional characterization of essential mechanosensitive ion channels, particularly the PIEZO family. By combining forward genetic screens, proximity-labeling proteomics, physiological assays, and transcriptomic analyses, we will identify the interactors and regulatory pathways modulating PIEZO-mediated mechanotransduction. These studies will enhance our understanding of how mechanotransduction influences cellular behavior, calcium-signaling pathways, and inter-tissue communication. The second direction investigates lipid metabolism, emphasizing de novo lipogenesis and lipid droplet (LD) formation — key processes for maintaining lipid homeostasis and supporting metabolic balance. Using genetic screens alongside advanced molecular and biochemistry approaches, we will identify novel genes that could genetically correct lipid metabolic defects, including imbalanced fatty acid synthesis and lipid toxicity, and uncover key regulatory proteins involved in de novo lipogenesis as well as the LD formation and dynamics. This work will define the genetic and molecular networks regulating lipid metabolism and examine how these processes sustain cellular functions under physiological and stress conditions. O ur long-term goal is to unravel these mechanistic connections and provide insights into mitigating the pathogenic impacts of mechanical stress and lipid accumulation, which exacerbate cellular and tissue damage in the liver, cardiac tissues, skeletal muscle, and beyond. Ultimately, this research aims to advance fundamental scientific knowledge and establish a foundation for translational applications. Project Number: 1R35GM162564-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Xiaofei Bai | Institution: UNIVERSITY OF FLORIDA, GAINESVILLE, FL | Award Amount: $320,750 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 CDB-E (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11270990