Novel mechanisms to increase beta cell regeneration by p27

p27 促进 β 细胞再生的新机制

• 批准号: 8662377
• 负责人: Senta K Georgia
• 金额: $ 10.88万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-10 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662377
• 关键词: Novel; mechanisms; increase; beta; cell

DESCRIPTION (provided by applicant): As of 2008, approximately 81 million people in the US have diabetes or pre-diabetes. As complications arising from diabetes represent the single largest cost to the US health care system, it is an imperative public health crisis to develop better therapies that treat, and potentially cure, the underlying cause of diabetes: hyperglycemia resulting from insufficient insulin production, due to either autoimmune destruction of insulin-producing beta cells or an inadequate mass of functional insulin-producing beta cells. This application seeks to improve our understanding of how to increase beta cell mass by investigating the mechanisms that govern the expansion of beta mass during embryogenesis and in response to diet-induced insulin resistance. Specifically, we propose to investigate how mechanisms that govern the accumulation or degradation of p27, a protein that functions to inhibit the expansion of beta cell mass, can be exploited to expand beta cell mass. We propose that Spy1A, a cell novel cell cycle regulator that can bypass p27-mediated inhibition of cell expansion, can be overexpressed to increase beta cell mass. We have also identified that Rap1A, a small GTPase activated during beta cell differentiation, may induce cell cycle arrest by upregulation of p27. We will use transgenic mouse models to investigate if spy1A overexpression or rap1A deletion can increase beta cell mass. We have discovered previously unidentified roles for skp2 and p27 in enteroendocrine differentiation from gut progenitor cells, which will serve as an alternative in vivo model to understand how beta cells may differentiate from adult progenitor cells to expand beta cell mass. We will use purified cell populations, cell culture models, lentiviral transfections, and siRNA knockdown experiments to assess how these proteins activate or repress p27 transcription and degradation. We expect that the results from the proposed aims of this grant will directly contribute to potential therapies to regenerate functional beta cell mass for diabetic patients. The theme of this research directly addresses the Beta Cell Therapy Research Program programmatic thrust of the NIDDK's division of Diabetes, Endocrinology and Metabolic Diseases. The research proposed in this grant will foster the transition of Dr. Senta K. Georgia from junior faculty to an independent research career. The theme of this grant is an extension of her established publication record in the field of beta cell differentiation and regeneration. Though she is building on her previous publication record, the experiments proposed in this application expose her to new techniques and new model systems for understanding beta cell differentiation and expansion. Under the mentorship of Dr. Mart¿n Mart¿n and co-mentorship of Dr. Anil Bhushan, Dr. Georgia will pursue cutting edge research at UCLA, with access to state-of-the-art equipment, cores, and resources to facilitate the production and analysis of data. In addition to her research, this proposal outlines specific mentorship activities that will foster Dr. Georgia's independence, including (but not limited to) attendance at new investigator workshops, presentation of her work at relevant international conferences, and detailed benchmarking of her progress by a personalized career development plan. We expect that the research proposed in this application will result in 3 high impact publications within the next 5 years that will advance the field of regenerative medicine and islet biology. With protected research time, freedom from the responsibility of didactic teaching responsibilities, participation in intellectually stimulating and education seminars, exposure to new model systems and new techniques, immersion in a stimulating and supportive environment, and active mentorship to encourage critical assessment of data and publication, we are very confident that Dr. Georgia will be an outstanding candidate for a tenure track independent research position at the end of the granting period of this award. PUBLIC HEALTH RELEVANCE: The 81 million Americans that are diabetic or are pre-diabetic suffer from the condition because the body's insulin-producing cells, either because of autoimmune destruction or the inability of the cells to function properly, are unable to maintain normal blood sugar levels. The proposed studies are targeted to understand how functional insulin-producing cells normally reproduce themselves. Results from these studies will contribute to the design of therapies to generate more insulin-producing cells as an effective cure for diabetes.

描述（由申请人提供）：截至2008年，美国约有8100万人患有糖尿病或糖尿病前期。由于糖尿病引起的并发症代表了美国医疗保健系统的最大单一成本，因此开发更好的治疗并可能治愈糖尿病的根本原因的治疗方法是一项紧迫的公共卫生危机：由于产生胰岛素的β细胞的自身免疫破坏或功能性产生胰岛素的β细胞的质量不足而导致的胰岛素产生不足引起的高血糖症。 本申请旨在通过研究在胚胎发生期间和对饮食诱导的胰岛素抵抗的反应中控制β细胞群扩张的机制来提高我们对如何增加β细胞群的理解。具体而言，我们建议研究如何管理的积累或降解的p27，蛋白质的功能，以抑制β细胞群的扩张，可以利用扩大β细胞群的机制。我们建议Spy 1A，一种可以绕过p27介导的细胞扩增抑制的细胞新细胞周期调节因子，可以过表达以增加β细胞质量。我们还发现Rap 1A是一种在β细胞分化过程中激活的小GT3，可能通过上调p27诱导细胞周期阻滞。我们将使用转基因小鼠模型来研究spy 1A过表达或rap 1A缺失是否会增加β细胞质量。我们已经发现了skp 2和p27在肠祖细胞肠内分泌分化中的作用，这将作为一种替代的体内模型来了解β细胞如何从成体祖细胞分化为扩大β细胞群。我们将使用纯化的细胞群，细胞培养模型，慢病毒转染和siRNA敲除实验来评估这些蛋白质如何激活或抑制p27转录和降解。我们预计，这项拨款的拟议目标的结果将直接有助于潜在的治疗方法，以再生糖尿病患者的功能性β细胞群。这项研究的主题直接涉及NIDDK糖尿病，内分泌学和代谢疾病部门的β细胞治疗研究计划。 这项资助中提出的研究将促进森塔K博士的过渡。格鲁吉亚从初级教师到独立的研究生涯。这项资助的主题是她在β细胞分化和再生领域的既定出版记录的延伸。虽然她是建立在她以前的出版记录，在这个应用程序中提出的实验使她接触到新的技术和新的模型系统，以了解β细胞分化和扩增。在Mart <$n Mart <$n博士和Anil Bhushan博士的共同指导下，格鲁吉亚博士将在UCLA进行尖端研究，并获得最先进的设备，核心和资源，以促进数据的生产和分析。除了她的研究，该提案概述了具体的指导活动，将促进格鲁吉亚博士的独立性，包括（但不限于）参加新的研究者研讨会，在相关的国际会议上介绍她的工作，并通过个性化的职业发展计划，她的进展的详细基准。 我们预计本申请中提出的研究将在未来5年内产生3篇高影响力的出版物，从而推动再生医学和胰岛生物学领域的发展。与受保护的研究时间，从教学责任的责任自由，在智力刺激和教育研讨会的参与，接触到新的模型系统和新技术，沉浸在一个刺激和支持性的环境，并积极辅导，以鼓励数据和出版物的批判性评估，我们非常有信心，格鲁吉亚博士将是一个杰出的候选人终身跟踪独立研究的立场，在年底授予期的这一奖项。 公共卫生相关性：有8100万美国人患有糖尿病或糖尿病前期，因为身体的胰岛素产生细胞，无论是由于自身免疫性破坏还是细胞无法正常运作，都无法维持正常的血糖水平。拟议的研究旨在了解功能性胰岛素产生细胞如何正常繁殖。这些研究的结果将有助于设计治疗方法，以产生更多的胰岛素产生细胞，作为有效治疗糖尿病的方法。