Understanding the transcriptional role of PPAR gamma in metabolic rewiring

转录因子是一种蛋白质，调节代谢途径中的基因表达，并决定细胞的功能、活性、细胞状态和细胞对环境的反应。过氧化物酶体增殖物激活受体(PPAR)是核受体超家族的转录因子。已经描述了三种异构体(α、β/β和伽马)。它们作为异源二聚体作用于DNA反应元件，与核维甲酸受体结合。它们的天然激活配体是脂肪酸和脂类底物。PPARγ是脂肪组织发育的关键成分，也是胰岛素增敏药物的靶点，在适应细胞内普遍存在的营养环境方面具有重要作用。它还被证明在免疫细胞分化和功能以及炎症控制中具有重要作用。然而，到目前为止，PPAR-γ调控的基因以及这种配体激活的转录因子的确切生物学功能尚不清楚，为了充分了解其作用机制，还需要进一步的探索。*我的研究计划旨在破译PPAR伽马调节的生物途径。我假设PPAR伽马在能量代谢途径和中间途径中发挥特定的调节作用，系统地绘制这些基因的转录调节网络将揭示它们的机制和途径的重要信息。*我目前项目的目标是了解PPAR伽马的作用机制的基本原理，以及重要的是它在能量代谢的转录调控中的作用，即糖酵解，以及相关的氧化磷酸化、脂肪代谢和氨基酸代谢的途径。*因此，我的工作将分析PPAR伽马如何与能量代谢途径相互作用，以确保动态平衡、细胞存活和正常的细胞功能。*未来5年所获得的结果将有助于实现我研究计划的长期目标，即探索PPAR伽马作用的图景。这将有助于发现PPAR伽马激活的新机制和途径以及十字路口。所开发的方法将是一种有效、高效和全面的技术，用于了解其他配体激活的转录因子的作用机制和途径。当应用于临床方面时，从长远来看，这些发现将成为改善2型糖尿病、癌症和几种神经疾病等症状的手段，这些疾病的病理生理涉及葡萄糖代谢和相关的中间途径。

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.**