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（由申请人提供）：Langerhans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。 Beta细胞活动或生存的功能障碍导致糖尿病梅洛蒂斯（Mellitus），这种疾病目前会影响美国人的数百万美元，预计将来的数量将大大增加，从而造成了巨大的经济和健康负担。改善糖尿病患者数量不断增长的结果的未来策略需要了解指定和区分功能性β细胞与祖细胞的复杂发育计划。利用对β细胞生物学中心的信号传导和转录事件的现有知识以及未来的理解将使您能够产生治疗性替代β细胞进行移植。这些目标的核心是假设，即由Lim域转录因子介导的转录过程所必需的重要辅助因子，以在发育和成人期间产生功能性β细胞。我的初步数据定义了胰腺中LDB1的表达模式以及LDB1在发育内分泌细胞中的作用。有条件地删除的小鼠证明，LDB1发育功能部分与胰腺中唯一良好研究的LIM因子（ISL1）重叠。这些目标将进一步定义由LDB1控制的ISL1依赖性和非依赖性遗传事件。 AIM 1将利用全基因组微阵列和CHIP-SEQ方法来阐明与观察到的表型相关的LDB1突变小鼠中调节的基因和途径。 AIM 2将测试LDB1相互作用的共同调节剂的体内作用，我还将利用一种创新的免疫沉淀程序来分离与其他组织相比，LDB1在胰腺中具有独特的相互作用因子，从而将新的LDB1相互作用因子与β细胞系中分离出来。有趣的新结合蛋白将在LDB1介导的转录对照中的作用进行测试。 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.我当前的环境非常适合我成功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，以回答这些目标提出的许多问题并产生有趣的数据，从而使我能够作为独立研究人员过渡到资金。