The Ldb1 coregulator controls LIM target genes in developing and adult islets.

Ldb1 核心调节器控制发育中和成年胰岛中的 LIM 靶基因。

• 批准号: 8803990
• 负责人: Chad S Hunter
• 金额: $ 6.51万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803990
• 关键词: Ldb1; coregulator; controls; LIM; target

DESCRIPTION (provided by applicant): Pancreatic beta cells within the Islets of Langerhans are required for glucose-stimulated insulin secretion and glucose homeostasis. Dysfunction in beta cell activity or survival results in diabetes mellitus, a disease currently affecting millionsof Americans with numbers expected to greatly increase in the future, thus creating an enormous economic and health burden. A future strategy to improve outcomes for the growing numbers of diabetic patients requires understanding the complex developmental programs that specify and differentiate functional beta cells from progenitors. Exploiting existing knowledge and future understanding of the signaling and transcriptional events central to beta-cell biology will allow u to produce therapeutic replacement beta cells for transplantation. Central to these Aims is the hypothesis that the important cofactor, Ldb1, is required for the transcriptional processes mediated by LIM-domain transcription factors to produce functional beta cells during development and in adults. My preliminary data defines the expression pattern of Ldb1 in the pancreas as well as the role of Ldb1 in developing endocrine cells. Conditionally deleted mice demonstrated that Ldb1 developmental function partially overlaps with the only well-studied LIM factor in the pancreas, Islet-1 (Isl1). These Aims will further define the Isl1-dependent and -independent genetic events controlled by Ldb1. Aim 1 will utilize genome-wide microarray and ChIP-Seq approaches to elucidate the genes and pathways regulated in Ldb1 mutant mice that correlate with the observed phenotype. Aim 2 will test the in vivo role of Ldb1-interacting co-regulators and I will also utilize an innovative immunoprecipitation procedure to isolate new Ldb1-interacting factors from beta cell lines, as I hypothesize that Ldb1 has unique interacting factors in the pancreas as compared to other tissues. Interesting new binding proteins will be tested for their role in Ldb1-mediated transcriptional control. Aim 3 will utilize animals lacking Ldb1 specifically in adult beta cells to define the roles of Ldb1 in adult islet function and targe gene control and determine the link with Isl1 and other known and newly identified interacting proteins tested in Aim 2. With this K01 Career Developmental Award, I will test my overall hypothesis that Ldb1 is required for all LIM complexes functioning in developing and adult islet cells. My current environment is uniquely suited for me to successfully initiate the proposed studies and complete my postdoctoral training. I will develop the tools and skills to answer many of the questions raised by these Aims and generate interesting data allowing me to transition into funding as an independent investigator.

描述（由申请方提供）：胰岛内的胰腺β细胞是葡萄糖刺激的胰岛素分泌和葡萄糖稳态所必需的。β细胞活性或存活的功能障碍导致糖尿病，糖尿病是一种目前影响数百万美国人的疾病，预计未来人数将大大增加，从而造成巨大的经济和健康负担。未来改善越来越多糖尿病患者预后的策略需要了解复杂的发育程序，这些程序指定并区分功能性β细胞和祖细胞。利用现有的知识和未来对β细胞生物学核心的信号和转录事件的理解，将使我们能够生产用于移植的治疗替代β细胞。这些目标的核心是假设重要的辅因子Ldb 1是由LIM结构域转录因子介导的转录过程所需的，以在发育期间和成人中产生功能性β细胞。我的初步数据定义了Ldb1在胰腺中的表达模式以及Ldb1在发育内分泌细胞中的作用。Conclusion缺失小鼠表明，Ldb1发育功能与胰腺中唯一经过充分研究的LIM因子Islet-1（Isl 1）部分重叠。这些目的将进一步明确Ldb1控制的Isl1依赖性和非依赖性遗传事件。目的1将利用全基因组微阵列和ChIP-Seq方法来阐明Ldb1突变小鼠中与观察到的表型相关的基因和途径。目的2将测试在体内的作用Ldb1相互作用的协同调节，我也将利用一种创新的免疫沉淀程序，以分离新的Ldb1相互作用的因子β细胞系，因为我假设，Ldb1具有独特的相互作用因子在胰腺相比，其他组织。有趣的新的结合蛋白将测试其在Ldb1介导的转录控制的作用。目标3将利用在成年β细胞中特异性缺乏Ldb 1的动物来确定Ldb 1在成年胰岛功能和靶基因控制中的作用，并确定与Isl 1和其他已知的和新鉴定的相互作用蛋白的联系。有了这个K01职业发展奖，我将测试我的总体假设，即Ldb1是所有LIM复合体在发育和成年胰岛细胞中发挥作用所必需的。我目前的环境非常适合我成功地启动拟议的研究，并完成我的博士后培训。我将开发工具和技能来回答这些目标提出的许多问题，并生成有趣的数据，使我能够作为独立调查员过渡到资金。