Grant: Discovery Grants Program - Individual

Transcription factors(TFs) are proteins that modulate gene expression in metabolic pathways and determine the functionality, viability, cellular state and a cell's response to the environment. Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the superfamily of nuclear receptors. Three isoforms (alpha, beta/delta and gamma) have been described. They act on DNA response elements as heterodimers with the nuclear retinoic acid receptor. Their natural activating ligands are fatty acids and lipid-derived substrates. PPAR gamma is a key component of adipose tissue development and a target of insulin-sensitizing drugs and has an important role in adaptation to the prevailing nutritional environment in the cell. It has also been shown to have important role in immune cell differentiation and function and inflammation control. However, till date the genes that PPAR gamma modulates and the exact biological functions of this ligand activated transcription factor are not known and further exploration is a must in order to fully understand the mechanism of action. My research program aims to decipher the biological pathways regulated by PPAR gamma. I hypothesize that PPAR gamma plays specific regulatory roles in pathways of energy metabolism and intermediate pathways and that a systematic effort to map the transcriptional regulatory network of these genes will reveal important information on their mechanisms and pathways. The objective of my current project is to understand the fundamentals of PPAR gamma's mechanism of action and importantly its role in transcriptional regulation of the energy metabolism i.e., glycolysis, and associated pathways of oxidative phosphorylation, lipid metabolism and amino acid metabolism. Thus, my work will analyze how PPAR gamma cross-talks with energy metabolism pathways to ensure homeostasis, cell viability and normal cellular functions.The results obtained over the next 5 years will contribute towards the long-term objective of my research program, which is to explore the landscape of the PPAR gamma action. It will help discern novel mechanisms and pathways and crossroads of PPAR gamma activation. The methodology developed will be an effective, efficient, and comprehensive technique for understanding mechanisms and pathways of action for other ligand activated transcription factors. When applied to clinical aspects, in the long run, the findings will be a means of improving syndromes such as type 2 diabetes, cancer and several neurological disorders whose pathophysiology involves glucose metabolism and related intermediate pathways.