The Role of NR5A2 in Pancreas Development and Disease

 描述（由申请人提供）：本提案描述了Sahar Nissim博士作为胃肠道疾病研究者实现独立性的五年培训计划。尼森博士是医学博士博士他是一名医生科学家，曾参加过NIH赞助的医学科学家培训计划，并在布里格姆妇女医院完成了胃肠病学的临床培训。他现在正着手进行一项研究和职业发展计划，该计划将建立在他严格的博士学位基础上。在哈佛医学院接受发育生物学培训。Nissim博士将在以下人员的共同指导下接受培训：Wolfram Goessling，医学博士，博士，布里格姆妇女医院和哈佛医学院的医学助理教授，他是使用斑马鱼研究内胚层发育和肝脏疾病的国际公认的领导者;和大卫科恩，医学博士，博士，布里格姆妇女医院肝病科主任和哈佛医学院医学教授，他是世界知名的肝脏脂质代谢专家，有着长期的成功指导记录。为了进一步指导他的研究和职业目标的完成，Nissim博士将定期与由Peter Banks博士，Cliff Tabin教授和Len Zon博士组成的科学咨询委员会会面，他们将分别提供胰腺疾病，发育生物学和斑马鱼方法学方面的专业知识。Nissim博士的职业发展计划包括在哈佛消化疾病中心和哈佛干细胞研究所的课程和合作。他详细列出了在同行评审期刊上发表他的工作、在国家会议上发表演讲以及发展独立研究项目和资助的明确时间轴。Nissim博士专注于为他在临床上看到的胰腺疾病（包括胰腺炎和胰腺癌）开发新的诊断和治疗策略。胰腺炎是美国住院的最常见的胃肠道原因，胰腺癌仍然是最致命的癌症之一。Nissim博士的研究计划旨在研究核受体5A 2（NR 5A 2）的功能和治疗潜力，该基因最近被全基因组关联研究所牵连，但其机制和对胰腺疾病的影响尚不清楚。在初步工作中，Nissim博士发现NR 5A 2在胰腺发育中起着关键作用，并且是外分泌胰腺细胞正常分化所必需的。此外，他发现这种发育作用可能与成人疾病有关，因为在外分泌细胞分化被破坏时，在胰腺炎和胰腺癌的背景下，NR 5A 2表达异常丢失。为了进一步探索这些发现，本提案的具体目的是（1）描述NR 5A 2在胰腺发育中的作用和途径相互作用，以及（2）测试在胰腺炎和胰腺癌的斑马鱼模型中调节NR 5A 2的功能影响。作为一种核受体，NR 5A 2将成为一个理想的药理学靶点，因此这项工作的发现对胰腺疾病患者的管理具有直接的转化潜力。

 DESCRIPTION (provided by applicant): This proposal describes a five-year training program for Dr. Sahar Nissim to achieve independence as an investigator in gastrointestinal disease. Dr. Nissim is an M.D.-Ph.D. physician scientist and prior trainee of the NIH-sponsored Medical Scientist Training Program, and has completed clinical training in Gastroenterology at the Brigham and Women's Hospital. He is now embarking on a research and career development program that will build on his rigorous Ph.D. training in developmental biology at the Harvard Medical School. Dr. Nissim will train under the co-mentorship of: Wolfram Goessling, M.D., Ph.D., Assistant Professor of Medicine at Brigham and Women's Hospital and Harvard Medical School who is an internationally-recognized leader in the study of endoderm development and liver disease using zebrafish; and, David Cohen, M.D., Ph.D, Director of Hepatology at the Brigham and Women's Hospital and Professor of Medicine at Harvard Medical School who is a world-renown expert in liver lipid metabolism with a long track record of successful mentorship. To further guide completion of his research and career goals, Dr. Nissim will meet regularly with a Scientific Advisory Committee comprised of Dr. Peter Banks, Professor Cliff Tabin, and Dr. Len Zon, who will provide expertise in pancreas disease, developmental biology, and zebrafish methodology, respectively. Dr. Nissim's career development plan incorporates coursework and collaboration at the Harvard Digestive Diseases Center and the Harvard Stem Cell Institute. He has detailed a clear timeline for publication of his work in peer-reviewed journals, presentations at national meetings, and development of independent research projects and funding. Dr. Nissim is focused on developing novel diagnostic and treatment strategies for pancreas diseases that he sees in the clinic, including pancreatitis and pancreatic cancer. Pancreatitis is the single most common gastrointestinal cause of hospital admission in the U.S., and pancreatic cancer remains one of the most lethal cancers. The objective of Dr. Nissim's research proposal is to investigate the function and therapeutic potential of Nuclear Receptor 5A2 (NR5A2), a gene recently implicated by a Genome-Wide Association Study but whose mechanism and impact on pancreas disease is not known. In preliminary work, Dr. Nissim has uncovered that NR5A2 plays a critical role in development of the pancreas and is required for normal differentiation of exocrine pancreas cells. Further, he has found that this developmental role may have relevance to adult disease, as NR5A2 expression is aberrantly lost in the context of pancreatitis and pancreatic cancer when exocrine cell differentiation is disrupted. To explore these findings further, the Specific Aims of this proposal are (1) to delineate the role and pathway interactions of NR5A2 in pancreas development, and (2) to test the functional impact of modulating NR5A2 in zebrafish models of pancreatitis and pancreatic cancer. As a nuclear receptor, NR5A2 would make an ideal pharmacologic target, and thus findings of this work have direct translational potential for management of patients with pancreas disease.