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

基本信息

批准号：
7474682
负责人：
John Michael Rukstalis
金额：
$ 13.72万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/7474682
关键词：
Address Adult Aftercare American Animal Model Apoptosis Apoptosis Regulator Apoptotic Attenuated Autoimmune Diabetes Autoimmune Process Beta Cell Blindness Cell Death Cell Line Cell Proliferation Cell Survival Cell physiology Cells Cessation of life Complication Cultured Cells Cytoplasm Development Diabetes Mellitus Diagnosis Disease Disruption Dominant-Negative Mutation DsRed Educational process of instructing Endocrine Endocrinology Event Family Family member Fostering Future General Hospitals Generations Glucose Goals Heart Hematopoietic stem cells Immunologics Immunosuppressive Agents In Vitro Inbred NOD Mice Individual Inflammatory Institution Insulin Insulin-Dependent Diabetes Mellitus Investigation Kidney Diseases Laboratories Learning Life Life Expectancy Ligands Massachusetts Metabolic stress Methodology Methods Mitochondria Molecular Mus Natural regeneration Nerve Numbers Pancreas Positioning Attribute Prevention Principal Investigator Process Protocols documentation Quality of life Recording of previous events Regulation Replacement Therapy Research Research Personnel Risk Role Scientist Signal Transduction Signal Transduction Pathway Snails Source Stem cells Stimulus Structure of beta Cell of islet Supervision System Techniques Testing Tetracycline Tetracyclines Therapeutic Tissues Training Transgenic Mice Transplantation Virus Diseases career cell motility cytochrome c cytokine diabetes management diabetic embryonic stem cell epithelial to mesenchymal transition exenatide glycemic control in vivo irradiation islet member mitochondrial membrane prevent programs protective effect response restoration skills slug stem tool transcription factor transgene expression

项目摘要

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综合医院的乔尔·哈贝纳（Joel Habener）实验室的成员。 Habener博士一直是糖尿病和内分泌学领域的领导者，已有30多年的历史，并拥有培训候选人的历史，成为成功的独立研究人员。同样，马萨诸塞州综合医院是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。我的职业目标是在接下来的2 - 3年的监督下完成我的培训，然后过渡到学术研究和教学机构的独立科学家的职位。我将受益于Habener博士的额外培训，以便我可以学习处理体内胰腺内分泌功能的方法和技术，以补充我目前的体外技能。我认为，必须发展在细胞培养和动物模型中有效发挥作用的能力，以便我可以正确解决与糖尿病的管理和治疗有关的问题。通过细胞凋亡失去β细胞质量是糖尿病发作和进展的重要事件。确定衰减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重大利益。我最近确定了胰腺β细胞中抗凋亡转录因子SLUG的表达，并假设Slug可以作为胰腺中的生存因子，与其在许多其他组织中的祖细胞中的功能相似。为了解决SLUG在胰腺中的作用，我建议：（1）分析培养的胰腺β细胞中SLUG的抗凋亡功能，（2）（2）调节体内的SLUG表达以保护β细胞免受凋亡的影响。我们希望，通过进一步了解调节β细胞存活功能的转录网络，可以开发治疗策略来促进和增加β细胞质量，以预防或治疗糖尿病。目前，超过2000万美国人患有糖尿病，预计该数字仅在可预见的将来增加。我们认为，通过了解调节β细胞存活的系统，我们可以开发用于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，对SLUG的实验操作将使我们能够维持或再生β细胞量以治疗糖尿病个体。