Understanding the transcriptional role of PPAR gamma in metabolic rewiring

了解 PPAR gamma 在代谢重连中的转录作用

• 批准号: RGPIN-2016-03956
• 负责人: Sakharkar, MEENA
• 金额: $ 4.52万
• 依托单位: University of Saskatchewan
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=762128
• 关键词: Understanding; transcriptional; role; PPAR; gamma

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.

转录因子（TF）是调节代谢途径中的基因表达并决定功能性、活力、细胞状态和细胞对环境的响应的蛋白质。 过氧化物酶体增殖物激活受体（PPARs）是属于核受体超家族的转录因子。已经描述了三种亚型（α、β/δ和γ）。它们作为异二聚体与核视黄酸受体作用于DNA反应元件。它们的天然活化配体是脂肪酸和脂质衍生的底物。PPARgamma是脂肪组织发育的关键成分，也是胰岛素增敏药物的靶点，在适应细胞中的主要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调节的基因和这种配体激活的转录因子的确切生物学功能尚不清楚，必须进一步探索，以充分了解作用机制。 我的研究项目旨在破译由PPARgamma调控的生物学途径。我假设PPAR γ在能量代谢途径和中间途径中发挥特定的调节作用，并且系统地绘制这些基因的转录调节网络将揭示有关其机制和途径的重要信息。我目前的项目的目标是了解PPARgamma的作用机制的基本原理，重要的是它在能量代谢的转录调节中的作用，即，糖酵解以及氧化磷酸化、脂质代谢和氨基酸代谢的相关途径。因此，我的工作将分析如何与能量代谢途径，以确保稳态，细胞活力和正常的细胞功能的交叉会谈。在未来5年内获得的结果将有助于我的研究计划的长期目标，这是探索景观的PPAR γ行动。它将有助于识别新的机制和途径以及PPAR γ激活的十字路口。开发的方法将是一个有效的，高效的，全面的技术，了解机制和其他配体激活的转录因子的作用途径。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，癌症和几种神经系统疾病等综合征的手段，这些疾病的病理生理学涉及葡萄糖代谢和相关的中间途径。