Inhibition of pancreatic beta cell apoptosis by the transcription factor Slug

转录因子 Slug 抑制胰腺 β 细胞凋亡

• 批准号: 7185535
• 负责人: John Michael Rukstalis
• 金额: $ 12.83万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-28 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7185535
• 关键词: NOD mouse; apoptosis; autoimmunity; cell line; cell proliferation; cytokine; cytoprotection; disease /disorder onset; gene induction /repression; genetically modified animals; glucose tolerance; hormone analog; incretin hormone; insulin dependent diabetes mellitus; laboratory mouse; pancreatic islet function; pathologic process; regeneration; reptile poison; tetracyclines; transcription factor; transfection

DESCRIPTION (provided by applicant): The applicant is a member of Dr. Joel Habener's laboratory at Massachusetts General Hospital. Dr. Habener has been a leader in the fields of diabetes and endocrinology for over 30 years and has a history of training candidates to be successful independent researchers. Likewise, Massachusetts General Hospital is vibrant and supportive research institution that actively strives to foster the development of academic scientists. My career goal is to complete my training under Dr. Habener's supervision for the next 2-3 years, and then transition to a position as an independent scientist at an academic research and teaching institution. I would benefit from additional training from Dr. Habener so that I may learn methodologies and techniques to manipulate pancreatic endocrine function in vivo to compliment my current in vitro skills. I believe that it is essential that I develop the ability to function effectively in both cell culture and animal models so that I may properly address questions relevant to the management and cure of diabetes mellitus. Loss of beta cell mass through apoptosis is a significant event in the onset and progression of diabetes. Identifying ways to attenuate apoptosis and promote cell survival could provide significant benefit to those afflicted with this disease. I have recently identified the expression of the anti-apoptotic transcription factor Slug in pancreatic beta cells and postulate that Slug may act as a prosurvival factor in the pancreas, similar to its function in progenitor cells in numerous other tissues. To address the role of Slug in the pancreas, I propose to: (1) analyze antiapoptotic function of Slug in cultured pancreatic beta cells, and (2) modulate Slug expression in vivo to protect beta cells from apoptosis. We hope that by further understanding the transcriptional networks which function to regulate beta cell survival, therapeutic strategies can be developed to promote and increase in beta cell mass for the prevention or treatment of diabetes. Over 20 million Americans currently suffer from diabetes mellitus, and that number is predicted to only increase in the foreseeable future. We believe that by understanding the systems regulating beta cell survival, we can develop methods to either prevent cell loss or promote beta cell regeneration. We hypothesize that the pro-survival factor Slug is a regulator of beta cell death, and experimental manipulation of Slug will allow us to maintain or regenerate beta cell mass in order to treat diabetic individuals.

描述（由申请人提供）： 申请人是马萨诸塞州总医院乔尔·哈本纳博士实验室的成员。 Habener 博士 30 多年来一直是糖尿病和内分泌学领域的领导者，并拥有培训候选人成为成功的独立研究人员的历史。同样，马萨诸塞州总医院是一个充满活力和支持性的研究机构，积极努力促进学术科学家的发展。我的职业目标是在哈本纳博士的指导下完成未来 2-3 年的培训，然后过渡到学术研究和教学机构担任独立科学家。我将受益于 Habener 博士的额外培训，以便我可以学习在体内操纵胰腺内分泌功能的方法和技术，以补充我目前的体外技能。我相信，我必须培养在细胞培养和动物模型中有效发挥作用的能力，这样我才能正确解决与糖尿病管理和治疗相关的问题。 通过细胞凋亡导致β细胞质量损失是糖尿病发病和进展的一个重要事件。找出减弱细胞凋亡和促进细胞存活的方法可以为患有这种疾病的人带来显着的益处。我最近发现了抗凋亡转录因子 Slug 在胰腺 β 细胞中的表达，并推测 Slug 可能充当胰腺中的促生存因子，类似于它在许多其他组织的祖细胞中的功能。为了解决 Slug 在胰腺中的作用，我建议：（1）分析 Slug 在培养的胰腺 β 细胞中的抗凋亡功能，（2）在体内调节 Slug 表达以保护 β 细胞免于凋亡。我们希望通过进一步了解调节β细胞存活的转录网络，可以开发出促进和增加β细胞质量的治疗策略，以预防或治疗糖尿病。 目前有超过 2000 万美国人患有糖尿病，并且预计这个数字在可预见的未来只会增加。我们相信，通过了解调节 β 细胞存活的系统，我们可以开发出防止细胞损失或促进 β 细胞再生的方法。我们假设促生存因子 Slug 是 β 细胞死亡的调节剂，Slug 的实验操作将使我们能够维持或再生 β 细胞质量，以治疗糖尿病个体。