Notch and Regulators of Notch Signaling Impact Both Glucose and Lipid Metabolism

Notch 和 Notch 信号调节因子影响葡萄糖和脂质代谢

• 批准号: 8526454
• 负责人: Utpal Pajvani
• 金额: $ 15.52万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526454
• 关键词: Ablation; Academic Medical Centers; Accounting; Address; Adipocytes; Adipose tissue; Animals; Apolipoproteins B; Biochemistry; Biology; Cancer Biology; Cells; Characteristics; Cholesterol; Clinical; Clinical Research; Communities; Data; Deposition; Development; Diabetes Mellitus; Diet; Doctor of Philosophy; Dyslipidemias; Endocrinology; Environment; Epidemiology; Euglycemic Clamping; Faculty; Family; Fasting; Fatty Liver; Five-Year Plans; Foundations; Fractionation; Funding; Gene Expression; Gene Expression Profiling; Gene Family; Gene Targeting; Genes; Genetic; Genetic Models; Glucose; Glucose Clamp; Goals; Growth; Hepatic; Hepatocyte; Homeostasis; Hormones; Human; Hyperglycemia; Hyperlipidemia; Inpatients; Insulin; Insulin Resistance; Internal Medicine; Knock-out; Knockout Mice; Knowledge; Leptin; Lipids; Lipolysis; Lipoproteins; Liver; Malignant Neoplasms; Measures; Mediating; Medical; Medicine; Mentors; Metabolic; Metabolic syndrome; Metabolism; Modeling; Modification; Monoclonal Antibodies; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obese Mice; Obesity; Other Genetics; Pathogenesis; Pathway interactions; Patient Care; Patients; Personal Satisfaction; Physicians; Pilot Projects; Plasma; Prevalence; Process; Public Health; Regulation; Research; Research Personnel; Research Training; Robin bird; Rodent; Role; Scientist; Seminal; Serum; Services; Signal Transduction; Skeletal Muscle; Statistical Methods; Stimulus; Techniques; Therapeutic; Therapeutic Agents; Tissues; Training; Transcriptional Regulation; Translating; Translational Research; Triglycerides; Universities; Work; adiponectin; bariatric surgery; base; bench to bedside; blood glucose regulation; carbohydrate metabolism; career; cohort; college; design; diabetic; diabetic patient; drug development; fatty acid oxidation; feeding; glucose disposal; glucose metabolism; glucose production; glucose tolerance; hepatic gluconeogenesis; improved; inhibitor/antagonist; insight; insulin sensitivity; insulin sensitizing drugs; insulin signaling; knockout animal; lipid biosynthesis; lipid metabolism; liver biopsy; loss of function; member; mouse model; nonalcoholic steatohepatitis; notch protein; novel; novel therapeutics; patient population; prevent; receptor; research study; secretase; small molecule; therapeutic target; tool; transcription factor; tumorigenesis; uptake

DESCRIPTION (provided by applicant): This proposal describes a five year plan for Utpal Pajvani to transition to an independently-funded investigator, a clinician/scientist with a focus on translational research. Dr. Pajvani received MD and PhD degrees from the Albert Einstein College of Medicine in 2005, the latter degree earned in defining the biochemistry of the adipocyte-secreted hormone, adiponectin, and subsequently performed medical training in Internal Medicine and Endocrinology at Columbia University. Dr. Pajvani's clinical training cemented his intent to translate research to benefit patients, whether it be through the discovery of a novel pathway in the development of insulin resistance, or application of a known therapeutic agent from cancer biology to the metabolic syndrome. The goals of the proposed training are to provide training and mentoring to prepare Dr. Pajvani for an independent research career, and additionally, to answer fundamental, lingering questions on the pathogenesis of insulin resistance and its treatment. Type 2 diabetes is associated with obesity and generalized insulin resistance; currently available insulin sensitizers are only partially effective at improving glucose disposal in skeletal muscle and suppressing glucose production in liver. A more detailed knowledge of pathways that influence insulin resistance is necessary to identify new targets for the development of drugs that will assist in the management of diabetic patients. In this application, Dr. Pajvani describes preliminary data that reveal the novel role of the Notch family of transmembrane receptors, traditionally thought only to mediate normal development and thereafter remain quiescent unless inappropriately activated in cancer, in regulation of hepatic metabolism through its interaction with FoxO1, a transcription factor known to modulate insulin sensitivity. Through detailed metabolic analyses in compound haploinsufficient (FoxO1:Notch1) mice, Dr. Pajvani and one of his mentors, Domenico Accili, determined that genetic inhibition of hepatic Notch action demonstrated beneficial effects in both glucose and lipid homeostasis. These effects were recapitulated by pharmacologic inhibitors of Notch action, which were able to markedly improve glucose tolerance in diet- induced and genetic models of obesity. Dr. Pajvani proposes in this application (i) to characterize the Notch pathway in states of insulin resistance, (ii) to determine the mechanism of the differential effects of Notch and its pharmacological inhibitors on glucose and lipid metabolism, and (iii) to study the effects of inhibition of Notch signaling with pharmacologic tools (small molecule inhibitors or monoclonal antibodies) or other genetic mouse models of Notch hypofunction. Additionally, Dr. Pajvani proposes an observational clinical study to determine if hepatic expression of Notch pathway components correlates with measures of insulin resistance, hyperlipidemia and/or hepatic steatosis in obese and diabetic patients. The goal of these studies is to demonstrate whether inhibition of Notch signaling is a viable therapeutic target in the correction of hyperglycemia and dyslipidemia characteristic of obesity-induced insulin resistance and the metabolic syndrome. Dr. Pajvani's overall career objective is to be able to translate the seminal discoveries made at the bench into therapeutic application in patients he sees at the Naomi Berrie Diabetes Center and inpatient Endocrinology and Metabolism service at Columbia University Medical Center. His patient care responsibilities, beyond providing personal satisfaction, allow Dr. Pajvani to approach scientific questions with pragmatism and with a sense of urgency. These same responsibilities encourage continued research training, as outlined in this application. The training he still needs to understand and fruitfully apply epidemiology and statistical methods in the design and analysis of clinical research studies, can best be addressed through continued study at Columbia University. Furthermore, the scientific knowledge required to integrate hepatic insulin signaling on glucose and lipid metabolism, as well as the multifaceted aspects of FoxO1 and Notch biology, can best be addressed through his choice of mentors (Drs. Domenico Accili and Jan Kitajewski) and advisors (Drs. Henry Ginsberg, Ira Goldberg and Robin Goland), all respected investigators who value mentoring young and aspiring faculty members. Finally, the Columbia University Medical Center environment brings together access to a diverse patient population and all the facilities and faculty developmental tools that Dr. Pajvani will need in order to become an independent translational medical researcher and a productive member of the academic medical community.

描述（由申请人提供）：该提案描述了 Utpal Pajvani 转型为独立资助的研究者、专注于转化研究的临床医生/科学家的五年计划。 Pajvani 博士于 2005 年在阿尔伯特·爱因斯坦医学院获得医学博士和博士学位，后者的学位是在定义脂肪细胞分泌激素脂联素的生物化学方面获得的，随后在哥伦比亚大学接受了内科和内分泌学的医学培训。 Pajvani 博士的临床培训巩固了他将研究转化为造福患者的意图，无论是通过发现胰岛素抵抗发展的新途径，还是将癌症生物学中的已知治疗剂应用于代谢综合征。拟议培训的目标是提供培训和指导，帮助 Pajvani 博士为独立研究生涯做好准备，此外，还回答有关胰岛素抵抗发病机制及其治疗的基本且挥之不去的问题。 2 型糖尿病与肥胖和全身胰岛素抵抗有关；目前可用的胰岛素增敏剂在改善骨骼肌中的葡萄糖处理和抑制肝脏中的葡萄糖产生方面仅部分有效。需要更详细地了解影响胰岛素抵抗的途径，以确定开发有助于糖尿病患者管理的药物的新靶点。在本申请中，Pajvani 博士描述了初步数据，这些数据揭示了跨膜受体 Notch 家族的新作用，传统上认为该家族仅介导正常发育，此后保持静止状态，除非在癌症中不适当激活，通过与 FoxO1 相互作用调节肝脏代谢，一种已知调节胰岛素敏感性的转录因子。通过对复合单倍体不足 (FoxO1:Notch1) 小鼠进行详细的代谢分析，Pajvani 博士和他的导师之一 Domenico Accili 确定，肝脏 Notch 作用的基因抑制对葡萄糖和脂质稳态均具有有益作用。 Notch 作用的药理学抑制剂重现了这些作用，能够显着改善饮食诱导和遗传肥胖模型中的葡萄糖耐量。 Pajvani 博士在本申请中建议 (i) 表征胰岛素抵抗状态下的 Notch 通路，(ii) 确定 Notch 及其药理学抑制剂对葡萄糖和脂质代谢的不同影响的机制，以及 (iii) 研究使用药理学工具（小分子抑制剂或单克隆抗体）或其他 Notch 功能减退的遗传小鼠模型抑制 Notch 信号传导的效果。此外，Pajvani 博士提出了一项观察性临床研究，以确定 Notch 通路成分的肝脏表达是否与肥胖和糖尿病患者的胰岛素抵抗、高脂血症和/或肝脂肪变性的测量相关。这些研究的目的是证明抑制Notch信号传导是否是纠正肥胖引起的胰岛素抵抗和代谢综合征的高血糖和血脂异常特征的可行治疗靶点。 Pajvani 博士的总体职业目标是能够将实验室的开创性发现转化为他在 Naomi Berrie 糖尿病中心和哥伦比亚大学医学中心住院内分泌和代谢服务部门接诊的患者的治疗应用。除了提供个人满意度之外，他的患者护理职责还使 Pajvani 博士能够以务实和紧迫感来处理科学问题。正如本申请中所述，这些相同的职责鼓励继续进行研究培训。他仍然需要接受培训，以了解并有效地应用流行病学和统计方法来设计和分析临床研究，这可以通过在哥伦比亚大学继续学习得到最好的解决。此外，通过他选择的导师（Domenico Accili 博士和 Jan Kitajewski 博士）和顾问（Domenico Accili 博士和 Jan Kitajewski 博士）可以最好地解决整合葡萄糖和脂质代谢上的肝脏胰岛素信号传导所需的科学知识，以及 FoxO1 和 Notch 生物学的多方面问题。亨利·金斯伯格 (Henry Ginsberg) 博士、艾拉·戈德伯格 (Ira Goldberg) 和罗宾·戈兰德 (Robin Goland) 博士）都是受人尊敬的研究人员，他们重视指导年轻且有抱负的教员。最后，哥伦比亚大学医学中心的环境汇集了多样化的患者群体以及 Pajvani 博士成为独立转化医学研究员和学术医学界富有成效的成员所需的所有设施和教师发展工具。