The incidence of obesity and overweight health stress in the United States and elsewhere has elevated dramatically in the last 50 years, increasing the risk of related health disorders including diabetes, cardiovascular disease and cancer. A comprehensive understanding of the underlying biological mechanisms that drive lipid storage and lipid mobilization is a critical piece in facing this challenge. The nematode Caenorhabditis elegans has emerged as a powerful model system in which to identify mechanisms of lipid homeostasis. A distinct advantage of this system is the ability to study mechanisms across tissues in the context of the intact organism. New evidence has emerged that the TGF-?/BMP-related ligand DBL-1 is required for normal lipid accumulation in C. elegans. Furthermore, DBL-1/BMP regulates fat accumulation in part by downregulation of insulin/IGF-1-like signaling (IIS). The goal of this proposal is to identify the mechanisms by which DBL-1/BMP regulates fat metabolism at the molecular, cellular, and organismal levels. The PI with a team of student researchers will capitalize on techniques in C. elegans genetics, molecular biology, and imaging, to address the following specific aims: (1) Decipher the autonomous and nonautonomous effects of Smad activation on lipid droplet morphology; (2) Determine DBL-1/BMP signaling functions in homeostatic processes; and (3) Identify novel genes that act downstream of the DBL-1/BMP pathway in lipid homeostasis. The proposed research incorporates genetic, molecular, cell biological, and imaging techniques to address the mechanisms and consequences of DBL-1/BMP regulation of metabolism. The C. elegans system is well-suited to these studies because the key signaling pathways and metabolic pathways are present and easily manipulated. The high degree of conservation of these pathways ensures that these studies will be relevant to human metabolism and energy homeostasis and their misregulation in obesity and related disorders. Importantly, this project will provide training opportunities for a graduate student and undergraduate students, who will gain hands-on experience in current techniques in genetics, molecular biology, and microscopy, and develop oral and written science communication skills through lab meetings and attendance at professional conferences. Strong STEM training will be an outcome.
The obesity epidemic in the United States is extremely costly, both financially and in regard to quality of living. A better understanding of the biological mechanisms involved in fat storage and mobilization will support the search for therapeutic targets and risk factors related to obesity. In this project, we will exploit the advantages of a simple model organism to uncover the conserved genetic and cellular mechanisms underlying fat metabolism and storage.
| Clark, James F; Meade, Michael; Ranepura, Gehan et al. (2018) Caenorhabditis elegans DBL-1/BMP Regulates Lipid Accumulation via Interaction with Insulin Signaling. G3 (Bethesda) 8:343-351 |
| Madaan, Uday; Yzeiraj, Edlira; Meade, Michael et al. (2018) BMP Signaling Determines Body Size via Transcriptional Regulation of Collagen Genes in Caenorhabditis elegans. Genetics 210:1355-1367 |
| Savage-Dunn, Cathy; Padgett, Richard W (2017) The TGF-? Family in Caenorhabditis elegans. Cold Spring Harb Perspect Biol 9: |
