Pancreatic Beta-Cell Regeneration: Expanding the functional Mass

描述(由申请人提供)： 2008年7月，我将作为全国第一个内科和临床遗传学联合实习生毕业。这一独特的机会告诉我，我可以如何将临床和科学工作结合起来，以促进患者护理。我认为大多数疾病都有遗传基础，要么是高渗透性等位基因(常染色体显性条件)的结果，要么是弱渗透性等位基因(低风险关联等位基因)的结果。在任何一种情况下，致病等位基因都是了解病理生理学基础机制的窗口，并代表潜在的治疗靶点。作为一名对糖尿病特别感兴趣的科学家，我将利用这种理解来指导我的研究。作为一名临床医生，我将为每周一次的内分泌遗传学诊所工作。随着时间的推移，临床将越来越关注低外显性风险等位基因，这些等位基因将用于指导针对患者的预防和治疗护理。从长远来看，我希望通过实验室的长凳研究和从直接患者护理中获得的见解来推进糖尿病的治疗。 这项建议描述了一项为期5年的研究计划，以获得(细胞生物学、胰岛(细胞生理学)和再生医学领域的专业知识。目前，导致(-细胞衰竭和(-细胞再生)的分子机制尚不清楚。这项研究计划集中于表征(-细胞复制的分子机制，识别促进(-细胞生长的小分子)，并阐明(-细胞的基本生理。随着对细胞再生潜在机制的更好理解，我们将对糖尿病的基本病理生理有更深入的了解。此外，这个研究项目为我提供了一个平台，让我开始独立调查的职业生涯。 这里提出的研究将在道格拉斯·梅尔顿博士的指导下进行，道格拉斯·梅尔顿博士是再生医学领域的一位成就卓著的研究员，具有糖尿病方面的专门知识。我会定期与合作者和顾问见面，回顾我的进步，为了促进我的职业发展，我还会参加科学课程，以拓宽我的知识和技能。最后，这项提议的成功和我的职业生涯将得益于干细胞和再生医学部和BWH遗传学部门所创造的非凡的研究环境。 公共卫生相关性：糖尿病及其相关并发症是全球卫生保健的主要负担。目前，口服治疗的价值通常是有限的，强化胰岛素治疗，即使是由最用心的患者进行，也无法避免大多数疾病相关的病理。这项建议的重点是利用胰岛(-)细胞的再生能力来预防疾病的发生和发展。

DESCRIPTION (provided by applicant): In July of 2008, I will graduate as the first joint internal medicine and clinical genetics trainee in the country. This unique opportunity informs my vision of how I can integrate clinical and scientific work in a way that will advance patient care. I believe most disease has a hereditary basis, either as a result of highly penetrant alleles (autosomal dominant conditions) or weakly penetrant alleles (low-risk association alleles). In either case, the causative alleles are a window into the mechanisms underlying the pathophysiology and represent potential therapeutic targets. As a scientist, with a specific interest in diabetes, I will use this understanding to direct my research. As a clinician, I will staff a weekly endocrine genetics clinic. Over time, the clinic will increasingly be focused on low penetrance risk alleles which will be used to guide patient-specific preventive and therapeutic care. In the long-term, I hope to advance the treatment of diabetes through laboratory-based bench research and through insights garnered from direct patient care. This proposal describes a 5-year research program to acquire expertise in the fields of ( cell biology, islet ( cell physiology, and regenerative medicine. At present, the molecular mechanisms that are responsible for (-cell failure and (-cell regeneration remain obscure. This research plan is focused on characterizing the molecular mechanisms of (-cell replication, on identifying small-molecules that promote (-cell growth and on elucidating the basic physiology of (-cells. With a better understanding of the underlying mechanisms of (-cell regeneration, we will acquire insight into the basic pathophysiology of diabetes. Furthermore, this research program provides a platform for me to launch a career as an independent investigator. The studies proposed here will be carried out under the mentorship of Douglas Melton Ph.D., an accomplished investigator in the field of regenerative medicine with specific expertise in Diabetes. I will have regular meetings with collaborators and advisors to review my progress and to promote my career advancement I will also participate in scientific courses to broaden my knowledge and skills. Finally, the success of this proposal and of my career will be fostered by the extraordinary research environment created by the consortium of the Stem Cell and Regenerative Medicine Department and the BWH Genetics Division. PUBLIC HEALTH RELEVANCE: Diabetes and its related complications are a major global health care burden. At present, oral therapy is typically of limited value and intensive insulin therapy, even when performed by the most attentive patients, fails to avert most disease related pathology. This proposal is focused on harnessing the regenerative capacity of islet (-cells to prevent the onset and progression of disease.