Transcriptional regulation of pancreas development and function

描述（由申请人提供）：这是响应NOT-OD-09-058（NIH宣布恢复法案资金用于竞争性修订申请的可用性）的竞争性补充。糖尿病是一种代谢紊乱，目前影响全球超过1.8亿人。所有形式的糖尿病的共同点是内分泌胰腺中功能性胰岛素产生细胞的逐渐丧失。因此，了解内分泌胰腺的发育、生长、存活和功能可能为这种疾病的治疗提供基本的见解。我们的研究表明， Isl-1转录因子在胰腺内分泌的这些过程中起着至关重要的作用。在我们的初步数据中，我们表明，一个已知的Isl-1共调节，Ldb 1，也需要内分泌细胞的分化和/或功能。因此，内分泌胰腺中缺乏Ldb 1的突变小鼠在3个月大时没有胰岛细胞，并且患有严重的高血糖症。相反，具有密切相关的Ldb 2的种系缺失的小鼠没有明显的表型。这种Ldb 1突变体对胰岛细胞形成的影响与我们对内分泌胰腺中缺乏Isl-1的小鼠的结果惊人地相似。基于这些发现，我们假设Ldb 1在胰岛细胞发育和成体细胞功能中介导Isl-1的作用。在与斯坦博士在范德比尔特大学的实验室的协调努力下，我们将 1)表征Ldb 1和Ldb 2在胰腺中的表达，2）阐明Ldb 1在调节内分泌细胞发育中的作用，3）检查Ldb 1如何调节成体细胞功能。CHOP为当地经济做出了巨大贡献。2008年，CHOP的业务在该地区创造和支持了16，882个工作岗位，CHOP的总经济影响超过59亿美元。此外，通过私人捐款、国家卫生研究院的资金和医院业务的拨款，CHOP获得的研究资助总额超过美国任何其他儿童医院-2007-2008财政年度为1.8亿美元。这项提议将创造四个就业机会（两个在CHOP，两个在范德比尔特大学）。通过这样做，资助这个有竞争力的补充将扩大我的父母R 01的范围，并允许创造就业机会，以改善我们的经济。 公共卫生：糖尿病是一种代谢紊乱，目前影响全球超过1.8亿人。替换丢失或功能不正常的细胞代表了治愈，治疗或预防糖尿病的最佳可能性。本申请中描述的实验将有助于描述控制细胞生长和发育的机制，并使我们更接近于产生用于细胞替代疗法的功能性细胞。

DESCRIPTION (provided by applicant): This is a competitive supplement in response to NOT-OD-09-058 (NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications). Diabetes is a metabolic disorder that currently affects over 180 million people worldwide. Common to all forms of diabetes is the gradual loss of functional insulin-producing ¿ cells in the endocrine pancreas. Thus, understanding the development, growth, survival and function of the endocrine pancreas may provide fundamental insight into treatments for this disease. Our studies have revealed that the Isl-1 transcription factor plays a crucial role in these processes in the endocrine pancreas. In our preliminary data, we show that a known Isl-1 co-regulator, Ldb1, is also required for the differentiation and/or function of endocrine cells. Thus, mutant mice lacking Ldb1 in the endocrine pancreas have no islet cells at 3 months of age and suffer from severe hyperglycemia. In contrary, mice with a germ-line deletion of closely related Ldb2 have no obvious phenotype. The effect of this Ldb1 mutant on islet cell formation is strikingly similar to our results with mice lacking Isl-1 in the endocrine pancreas. Based on these findings, we hypothesize that Ldb1 mediates Isl-1 action during islet cell development and in adult ¿ cell function. In a coordinated effort with Dr. Stein's laboratory at Vanderbilt University, we will 1) characterize Ldb1 and Ldb2 expression in the pancreas, 2) elucidate the role of Ldb1 in regulating endocrine cell development, and 3) examine how Ldb1 regulates adult ¿ cell function. CHOP contributes substantially to the local economy. In 2008, CHOP's operations created and supported over 16,882 jobs in the region, and CHOP's total economic impact was over $5.9 billion. Moreover, through a combination of private donations, NIH funding, and allocations from its hospital operations, CHOP receives more total research support than any other children's hospital in the United States--$180 million in fiscal year 2007-2008. This proposal will create four jobs (two at CHOP and two at Vanderbilt University). By doing so, funding this competitive supplement will expand the scope of my parent R01 and allow for job creation to improve our economy. PUBLIC RELEVANCE HEALTH: Diabetes mellitus is a metabolic disorder that current affects over 180 million people worldwide. Replacement of lost or improperly functioning ¿-cells represents the best possibility to cure, treat, or prevent diabetes. The experiments described in this application will help delineate the mechanisms controlling the growth and development of ¿-cells and bring us closer to generating functional ¿-cells for cell replacement therapy.