Modulation of PPAR-gamma phosphorylation at S273 regulates insulin sensitivity

调节 PPAR-gamma S273 磷酸化可调节胰岛素敏感性

• 批准号: 8662862
• 负责人: ALEXANDER BANKS
• 金额: $ 8.51万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662862
• 关键词: Modulation; PPAR; gamma; phosphorylation; S273; Modulation; PPAR; gamma; phosphorylation; S273

DESCRIPTION (provided by applicant): PPAR-gamma is the target of highly effective but controversial diabetes medications, the thiazolidinediones. We recently demonstrated that these drugs reverse insulin resistance through a previously unappreciated mechanism-reversing an inhibitory PPAR-gamma-phosphorylation event. Phosphorylation of PPAR-gamma at serine 273 occurs shortly after the onset of high fat diet feeding and increases with progressive obesity. This phosphorylation correlates with dysregulation of PPAR-gamma target genes, such as adiponectin. Treatment of patients or mice with thiazolidinediones reverses phosphorylation as it improves insulin sensitivity. Utilizing a new mouse model we will investigate whether preventing this obesity-mediated PPAR-gamma S273 phosphorylation will alter adipose tissue morphology, gene expression and systemic insulin-sensitivity in vivo. To do this, we have generated mice with an adipose-specific knock-out of the relevant PPAR-gamma kinase, Cdk5. We predict that these mice will be a model of healthy obesity due to insulin-sensitive adipose tissue. Following the induction of diet-induced obesity in these mice, we will examine body composition, glucose homeostasis and PPAR-gamma target gene expression in adipose tissue from obese mice. We will compare the metabolic and transcriptional consequences of treating wild type Cdk5 KO mice treated with full agonists such as rosiglitazone against non-agonists such as SR1664. Furthermore, we will examine whether a diabetes susceptibility gene, Cdkal1, regulates PPAR-gamma S273 phosphorylation and adipocyte gene expression in mouse and human cells. This proposal defines a new mechanism whereby selectively targeting PPAR-gamma S273 phosphorylation may allow for specifically promoting the beneficial effects of PPAR-gamma activation without the adverse effects. The candidate, Dr. Alexander Banks, has a strong track record of innovative research with a focus on generating and characterizing genetically modified mouse models of human metabolic disease. He has performed postdoctoral training at Columbia and Harvard Universities and has experience in the study of mammalian physiologic response to aging, obesity, and diabetes. The candidate's career goal is to become an independent academic investigator and faculty mentor with a research laboratory contributing towards understanding and reversing metabolic diseases. This research will be conducted in the laboratory of Bruce Spiegelman, PhD at Harvard Medical School, who is a leader in field of molecular diabetes research. Co-mentorship will be contributed by David Altshuler, MD, PhD also of Harvard Medical School. Career development activities to augment the training experience include instruction using cutting-edge methods, attending scientific meetings, and the support of a scientific advisory committee with broad expertise in relevant subjects.

描述（由申请人提供）：PPAR-GAMMA是高效但有争议的糖尿病药物，即噻唑烷二酮的目标。我们最近证明，这些药物通过先前未欣赏的机制逆转胰岛素抵抗，从而逆转抑制性PPAR-GAMMA磷酸化事件。丝氨酸273处PPAR-gamma的磷酸化发生在高脂饮食喂养发作后不久，随着肥胖症的进行性肥胖。这种磷酸化与PPAR-GAMMA靶基因（例如脂联素）的失调相关。用噻唑烷二酮治疗患者或小鼠会在提高胰岛素敏感性时逆转磷酸化。利用新的小鼠模型，我们将研究这种肥胖介导的PPAR-GAMMA S273磷酸化是否会改变体内脂肪组织形态，基因表达和全身胰岛素敏感性。为此，我们生成了相关PPAR-GAMMA激酶CDK5的脂肪特异性敲除小鼠。我们预测，由于胰岛素敏感的脂肪组织，这些小鼠将成为健康肥胖的模型。在这些小鼠诱导饮食诱导的肥胖症之后，我们将检查体内组成，葡萄糖稳态和PPAR-GAMMA靶基因在肥胖小鼠的脂肪组织中的表达。我们将比较用全部激动剂（例如罗格列酮）对针对非激动剂（例如SR1664）处理的野生型CDK5 KO小鼠的代谢和转录后果。此外，我们将检查糖尿病易感性基因CDKAL1是否调节小鼠和人类细胞中PPAR-GAMMA S273磷酸化和脂肪细胞基因表达。该建议定义了一种新的机制，从而有选择地靶向PPAR-GAMMA S273磷酸化可能允许专门促进PPAR-GAMMA激活的有益效应而不会产生不利影响。候选人亚历山大·班克斯（Alexander Banks）博士拥有创新研究的良好记录，重点是产生和表征人类代谢疾病的转基因小鼠模型。他曾在哥伦比亚和哈佛大学进行过博士后培训，并在研究哺乳动物的生理反应方面对衰老，肥胖和糖尿病有经验。候选人的职业目标是成为一名独立的学术研究员和教师导师，并为理解和逆转代谢疾病做出贡献的研究实验室。这项研究将在哈佛医学院的布鲁斯·斯皮格曼（Bruce Spiegelman）实验室进行，他是分子糖尿病研究领域的领导者。同样，哈佛医学院的David Altshuler，医学博士David Altshuler将贡献会议。为了增强培训经验的职业发展活动包括使用尖端方法的教学，参加科学会议，以及在相关学科方面具有广泛专业知识的科学咨询委员会的支持。