Genetics of Beta Cell Failure in Mexican Americans

n主要研究项目主管（最后，第一，中间）：布坎南，托马斯A.描述：说明申请的广泛，长期目标和具体目的，参考项目的健康关系。简要描述为实现这些目标的研究设计和方法。避免总结过去的成就和使用第一人称。当与应用程序分离时，此摘要旨在作为对所建议工作的简洁而准确的描述。如果该应用程序获得资助，则此描述将成为公共信息。因此，不要包含专有/机密信息。不要超过规定的空间。在怀孕期间发生妊娠期糖尿病（GDM）的年轻西班牙女性中，我们发现相对早发性和进行性胰岛素分泌丧失先于并预测2型糖尿病（T2DM）的发展。胰岛素分泌缺陷似乎是由胰岛素抵抗引起或加重的，并且在GDM先证家族中具有高度遗传性。基于这些观察结果，我们假设存在导致这些年轻女性发生2型糖尿病的胰岛素分泌缺陷的遗传决定因素。我们在西班牙裔美国人的大型队列（包括一个大型家庭队列）中，在详细表型分析以量化胰岛素分泌和胰岛素抵抗方面有丰富的经验。我们也有机会接触到大量有GDM先证者的大家庭。因此，我们建议使用详细的表型分析结合候选基因和全基因组QTL连锁分析来寻找我们已经确定的b细胞缺陷的遗传决定因素。本研究的重点是墨西哥裔美国女性GDM患者及其兄弟姐妹和表亲（即具有b细胞缺陷的家庭）的招募和表型分析，以及在怀孕期间保持正常糖耐量（强大的b细胞功能）的匹配对照女性。所有这些人都将接受详细的b细胞功能、胰岛素敏感性和身体成分研究。其他家庭成员将提供DNA，用于评估血统身份，并用于将来构建GDM先证和匹配对照的单倍型。在此奖励期间，将对GDM和T2DM的候选基因进行研究。对全基因组扫描的支持将单独寻求，随后将对候选区域和基因进行精细的定位和关联研究。最终，该项目的结果对于实现我们的长期目标(a)了解年轻西班牙裔美国人2型糖尿病的根本原因(s)和(b)制定策略，在其演变的相对早期阶段预测和预防该疾病至关重要。网站性能 ======================================== 节结束 ===========================================

n Principal InvestigatodProgram Director (Last, first, middle): Buchanan, Thomas A. DESCRIPTION: State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project. Describe concisely the research design and methods for achieving these goals. Avoid summaries of past accomplishments and the use of the first person. This abstract is meant to serve as a succinct and accurate description of the proposed work when separated from the application. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED ]HE SPACE PROVIDED. In young Hispanic women who developed gestational diabetes mellitus (GDM) during pregnancy, we have identified relatively early-onset and progressive loss of insulin secretion that precedes and predicts the development of type 2 diabetes mellitus (T2DM). The defect in insulin secretion appears to be caused or worsened by insulin resistance and it is highly heritable in families of GDM probands. Based on these observations, we hypothesize that there are genetic determinants of the defect in insulin secretion that leads to T2DM in these young women. We have extensive experience with the performance of detailed phenotyping to quantify insulin secretion and insulin resistance in large cohorts of Hispanic Americans, including one large family-based cohort. We also have access to a large number of large families with a GDM proband. Accordingly, we propose to search for genetic determinants of the B-cell defect that we have identified, using detailed phenotyping combined with candidate gene and genome-wide QTL linkage analysis. The present proposal is focused on the recruitment and phenotyping of Mexican American women with GDM and their siblings and first cousins (i.e., families enriched with the B-cell defect) and of matched control women who maintained normal glucose tolerance during pregnancy (robust B-cell function). All of these individuals will have detailed studies of B-cell function, insulin sensitivity and body composition. Additional family members will provide DNA for assessment of ideniity-by-descent and for future construction of haplotypes in GDM probands and matched controls. Studies of selected candidate genes for GDM and T2DM will be conducted during this award period. Support for a genome-wide scan will be sought separately and will be followed by fine mapping and association studies of positional candidate regions and genes. Ultimately, the results of this project will be crucial in attaining our long-term goals of (a) understanding the fundamental cause(s) of T2DM in young Hispanic Americans and (b) developing strategies to predict and prevent that disease at relatively early stages in its evolution. PERFORMANCE SITE ========================================Section End===========================================