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

描述(由申请人提供)：本提案描述了Utpal Pajvani过渡到独立资助的研究人员、专注于转化性研究的临床医生/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和博士学位，后者获得的学位是定义脂肪细胞分泌的激素脂联素的生物化学，随后在哥伦比亚大学接受内科和内分泌学医学培训。帕伊瓦尼博士的临床培训巩固了他将研究转化为惠及患者的意图，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，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的发病机制及其治疗的根本性、挥之不去的问题。2型糖尿病与肥胖和全身性胰岛素抵抗有关；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只有部分有效。需要对影响胰岛素抵抗的途径有更详细的了解，以确定有助于糖尿病患者管理的药物开发的新靶点。在这项申请中，Pajvani博士描述了揭示Notch跨膜受体家族的新角色，该家族传统上被认为只参与正常发育，此后保持静止，除非在癌症中被不适当地激活，否则它通过与FoxO1相互作用调节肝脏代谢，FoxO1是一种已知调节胰岛素敏感性的转录因子。通过对化合物单倍体不足(FoxO1：NOTCH1)小鼠的详细代谢分析，Pajvani博士和他的一位导师Domeico Accili确定，对肝脏Notch作用的遗传抑制在血糖和血脂动态平衡方面都显示出有益的影响。Notch作用的药物抑制剂可以显著改善饮食诱导和遗传肥胖模型中的糖耐量，从而概括了这些效应。Pajvani博士建议在这一应用中(I)表征胰岛素抵抗状态下的Notch途径，(Ii)确定Notch及其药物抑制剂对葡萄糖和脂肪代谢的不同影响的机制，以及(Iii)利用药物工具(小分子抑制剂或单抗)或其他Notch功能低下的遗传小鼠模型来研究抑制Notch信号的效果。此外，Pajvani博士建议进行一项观察性临床研究，以确定肥胖和糖尿病患者的肝脏Notch途径组件的表达是否与胰岛素抵抗、高脂血症和/或肝脏脂肪变性的测量相关。这些研究的目的是证明抑制Notch信号是否是纠正肥胖引起的胰岛素抵抗和代谢综合征所特有的高血糖和血脂异常的可行治疗靶点。Pajvani博士的整个职业目标是能够将在工作台上取得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患者内分泌学和新陈代谢服务中的治疗应用。帕伊瓦尼的病人护理职责，除了提供个人满意度之外，还让他能够以实用主义和紧迫感处理科学问题。这些同样的责任鼓励继续进行研究培训，如本申请所述。他仍然需要在临床研究研究的设计和分析中理解和有效地应用流行病学和统计学方法，这方面的培训最好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肪代谢所需的科学知识，以及FoxO1和Notch生物学的多方面方面，可以通过他选择的导师(Domeico Accili博士和Jan Kitajesski博士)和顾问(Henry Ginsberg博士、Ira Goldberg博士和Robin Goland博士)最好地解决，这些都是受人尊敬的研究人员，他们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将帕伊瓦尼博士成为一名独立的转化型医学研究人员和学术医学界富有成效的成员所需的所有设施和教职员工发展工具集中在一起。

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.