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

描述（由申请人提供）：该提案描述了Utpal Pajvani过渡到独立资助的研究者，临床医生/科学家的五年计划，重点是转化研究。Pajvani博士于2005年获得阿尔伯特·爱因斯坦医学院的医学博士和博士学位，后者在定义脂肪细胞分泌激素脂联素的生物化学方面获得学位，随后在哥伦比亚大学进行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，还是将已知的治疗剂从癌症生物学应用于代谢综合征。拟议培训的目标是提供培训和指导，为Pajvani博士的独立研究生涯做好准备，并回答有关胰岛素抵抗及其治疗的发病机制的基本问题。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置和抑制肝脏中的葡萄糖产生方面仅部分有效。更详细地了解影响胰岛素抵抗的途径是必要的，以确定新的目标，开发药物，将有助于糖尿病患者的管理。在本申请中，Pajvani博士描述了初步数据，这些数据揭示了Notch跨膜受体家族的新作用，传统上认为Notch家族仅介导正常发育，此后保持静止，除非在癌症中被不适当地激活，通过与FoxO 1（一种已知调节胰岛素敏感性的转录因子）的相互作用来调节肝脏代谢。通过对复合单倍不足（FoxO 1：Notch 1）小鼠的详细代谢分析，Pajvani博士和他的导师之一Domenico Accili确定，对肝脏Notch作用的遗传抑制在葡萄糖和脂质稳态方面都表现出有益的作用。这些作用被Notch作用的药理学抑制剂概括，其能够显著改善饮食诱导的肥胖和遗传模型中的葡萄糖耐量。Pajvani博士在本申请中提出（i）表征胰岛素抵抗状态下的Notch途径，（ii）确定Notch及其药理学抑制剂对葡萄糖和脂质代谢的差异效应的机制，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Notch功能减退的其他遗传小鼠模型抑制Notch信号传导的效应。此外，Pajvani博士提出了一项观察性临床研究，以确定Notch途径组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/或肝脏脂肪变性的测量值相关。这些研究的目的是证明抑制Notch信号传导是否是纠正肥胖诱导的胰岛素抵抗和代谢综合征特征性高血糖和血脂异常的可行治疗靶点。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的住院内分泌和代谢服务中看到的患者的治疗应用。他的病人护理责任，除了提供个人满意度，让Pajvani博士以实用主义和紧迫感来处理科学问题。这些相同的责任鼓励继续研究培训，如本申请所述。他仍然需要在临床研究的设计和分析中理解和有效应用流行病学和统计方法的培训，可以通过在哥伦比亚大学继续学习来解决。此外，整合肝脏胰岛素信号对葡萄糖和脂质代谢的影响所需的科学知识，以及FoxO 1和Notch生物学的多方面问题，可以通过他选择的导师（Domenico Accili博士和Jan Kitauburski博士）和顾问（亨利金斯伯格博士，伊拉戈德堡和罗宾戈兰德）得到最好的解决，所有受人尊敬的研究人员都重视指导年轻和有抱负的教职员工。最后，哥伦比亚大学医学中心的环境汇集了访问不同的患者群体和所有的设施和教师发展工具，Pajvani博士将需要成为一个独立的转化医学研究人员和学术医学界的生产成员。

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.