Molecular mechanisms of fatty acid uptake and trafficking in renal tubule epithelial cells

The National Science Foundation Office of Integrative Activities awarded The Morehouse School of Medicine $985,378 on August 1, 2026, under the Integrative Activities program (CFDA 47.083) to investigate molecular mechanisms of fatty acid uptake and trafficking in renal tubule epithelial cells.

The research examines how kidney tubular epithelial cells use intracellular organelles to respond to energy and nutrient overloads, with focus on lipotoxicity—cellular dysfunction caused by accumulation of saturated fatty acids, particularly palmitate. The project applies biochemical, molecular biology, genetics, and genomics approaches to determine how signaling pathway components communicate to maintain cellular homeostasis and to advance understanding of molecular mediators and pathways involved in fatty acid uptake, trafficking, and metabolism. The work includes educational and training opportunities for middle school, high school, undergraduate, and graduate students in biological sciences to expand the STEM workforce.

Performance occurs in Atlanta, Georgia, with a period of performance from August 1, 2026, through July 31, 2030. The Integrative Activities program supports capacity-building and broadened participation in research and education to enhance the Nation's research competitiveness and develop critical infrastructure for the STEM enterprise.

Abstract

For cells to survive, they must keep their internal environment stable and balanced. How mammalian epithelial cells maintain a stable, healthy state under conditions of excess energy and nutrients remains unclear. The kidney is an essential organ for maintaining a body?s balanced environment by removing waste and extra fluids from the body. This project will examine how kidney tubular epithelial cells use multiple intracellular structures termed organelles to come together to respond to different energy overloads. Results learned will provide new knowledge and advance the understanding of molecular mediators and signaling pathways involved in fatty acid uptake, trafficking and metabolism. A range of biochemical, molecular biology, genetics and genomics approaches will be utilized to determine how components from different signaling pathways communicate to maintain a cell?s steady state. This project will provide middle, high school, undergraduate and graduate students with training and educational opportunities in biological sciences, allowing them to further pursue stem careers with the ultimate goal of enhancing the US scientific workforce. This project advances NSF?s priorities in biotechnology. Fatty acid oxidation provides the major source of energy supply for renal proximal tubule epithelial cells (ptecs); nevertheless, the accumulation of oversupplied fatty acids (FA), particularly the saturated FA palmitate, might lead to cellular dysfunction and apoptotic cell death, commonly referred to as ?lipotoxicity?. Thus, tight homeostatic control of palmitate concentration is important for normal ptec function. However, the mechanism(s) for maintaining lipid homeostatic balance under albumin-FA overload due to metabolic oversupply is not well understood. Kidney injury molecule-1 (KIM-1) expression on the apical membrane of ptec acts as a scavenger receptor for the binding and endocytosis of oxidized lipids, albumin and albumin-bound palmitate. This project aims to examine the underlying roles and molecular crosslinks between KIM-1-mediated endocytosis and intracellular signaling pathways related to mitochondria, endoplasmic reticulum and autophagy function in ptec lipid metabolism. Tempo-spatial distribution of KIM-1 and lipid accumulation in human ptec organoids will be compared with kidneys of KIM-1-deficient mice to elucidate the regulation of KIM-1 expression and its role in lipid homeostasis. Multiple techniques, including biological imaging (confocal and light sheet microscopy), western blotting, real-time PCR and RNA sequencing (RNA-SEQ), and lipotomics, will be used to examine the signaling pathways underlying KIM-1-mediated FA endocytosis and lipid metabolism. This work will advance fundamental understanding of the molecular and physiological basis of lipid dysregulation and guide innovative drug interventions and lifestyle modifications to effectively address lipid oversupply-related disorders. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the foundation's intellectual merit and broader impacts review criteria.- subawards are not planned for this award.