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向独立资助的研究者，专注于转化研究的临床医生/科学家过渡的五年计划。他于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，后一个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进行了内科和内分泌学的医学培训。Pajvani博士的临床培训强化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药物应用于代谢综合征。拟议培训的目标是为Pajvani博士提供培训和指导，为其独立的研究生涯做好准备，此外，还将回答有关胰岛素抵抗发病机制及其治疗的基本问题。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理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，这有助于确定开发有助于糖尿病患者管理的药物的新靶点。在这项应用中，Pajvani博士描述了初步数据，揭示了跨膜受体Notch家族的新作用，传统上认为它只介导正常发育，此后保持沉默，除非在癌症中被不适当地激活，通过与fox01（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，基因抑制肝脏Notch作用对葡萄糖和脂质稳态都有有益的影响。这些作用被Notch作用的药理学抑制剂所概括，它能够显著改善饮食诱导和遗传肥胖模型中的葡萄糖耐量。Pajvani博士在本申请中提出(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差异作用的机制，（iii）研究用药理学工具（小分子抑制剂或单克隆抗体）或其他Notch功能低下的遗传小鼠模型抑制Notch信号的作用。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/或肝脂肪变性相关。这些研究的目的是证明Notch信号的抑制是否是一个可行的治疗靶点，以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。Pajvani博士的总体职业目标是能够将他在Naomi Berrie糖尿病中心和哥伦比亚大学医学中心（Columbia University Medical Center）内分泌与代谢中心（Endocrinology and Metabolism）的住院病人身上看到的开创性发现转化为治疗应用。他的病人护理职责，除了提供个人满意度之外，还允许帕杰瓦尼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，概述在这个应用程序。他仍然需要在临床研究的设计和分析中理解和有效地应用流行病学和统计方法，最好通过在哥伦比亚大学的继续学习来解决。此外，整合肝脏胰岛素信号对葡萄糖和脂质代谢的科学知识，以及fox01和Notch生物学的多面性，可以最好地通过他选择的导师来解决。Domenico Accili和Jan Kitajewski)和顾问(dr。亨利·金斯伯格，艾拉·戈德堡和罗宾·戈兰)，他们都是受人尊敬的研究者，重视指导年轻而有抱负的教员。最后，哥伦比亚大学医学中心的环境汇集了各种各样的患者群体，以及Pajvani博士成为独立的转化医学研究人员和学术医学界富有成效的成员所需要的所有设施和教师发展工具。

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. PUBLIC HEALTH RELEVANCE: The increasing prevalence of obesity and Type 2 diabetes is a looming public health challenge in the next few decades. My research goal is to explore a novel therapeutic pathway to treat insulin resistance, based on my preliminary work that shows a role in this process for inappropriate activation of developmental pathways regulated by the Notch family of genes. In the process, my training aims are to become acquainted with techniques for the study of lipid metabolism and to design and properly interpret clinical studies demonstrating a correlation between aberrant Notch signaling and hepatic insulin resistance. The proposed work will provide new insight into treatment for the metabolic syndrome and allow me to develop into an independent academic physician/scientist.