Genetics of Beta Cell Failure in Mexican Americans

N首席研究项目主任(最后、第一、中间)：布坎南，Thomas A.描述：说明应用程序的广泛、长期目标和具体目标，并参考项目与健康的相关性。简明扼要地描述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。此摘要的目的是在脱离应用程序时，作为对拟议工作的简洁和准确的描述。如果申请得到资助，这一描述将成为公开信息。因此，不包括专有/机密信息。请勿超过所提供的空间。在怀孕期间患妊娠期糖尿病(GDM)的年轻西班牙裔妇女中，我们发现相对较早发病的和进行性的胰岛素分泌丧失是2型糖尿病(T2 DM)发展的先兆和预测。胰岛素分泌缺陷似乎是由胰岛素抵抗引起或恶化的，它在妊娠期糖尿病先证者家族中具有高度的遗传性。基于这些观察结果，我们假设在这些年轻女性中存在导致T2 DM的胰岛素分泌缺陷的遗传决定因素。我们在进行详细的表型分析以量化大量拉美裔美国人的胰岛素分泌和胰岛素抵抗方面有丰富的经验，其中包括一个以家族为基础的大型队列。我们还可以接触到大量有妊娠期糖尿病先证者的大家庭。因此，我们建议使用详细的表型结合候选基因和全基因组QTL连锁分析来寻找我们已经识别的B细胞缺陷的遗传决定因素。本提案的重点是招募患有妊娠期糖尿病的墨西哥裔美国妇女及其兄弟姐妹和近亲(即B细胞缺陷丰富的家庭)和在怀孕期间保持正常糖耐量(B细胞功能强大)的匹配对照组妇女的表型。所有这些人都将对B细胞功能、胰岛素敏感性和身体成分进行详细研究。更多的家庭成员将提供DNA，用于评估GDM先证者和配对对照的血统一致性，并用于未来单倍型的构建。在此获奖期间，将对GDM和T2 DM的选定候选基因进行研究。将单独寻求对全基因组扫描的支持，随后将对位置候选区域和基因进行精细绘制和关联研究。最终，该项目的结果将对实现我们的长期目标至关重要：(A)了解年轻的西班牙裔美国人T2 DM的根本原因(S)，以及(B)制定在疾病演变的相对早期阶段预测和预防该疾病的策略。表演网站========================================Section End===========================================

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===========================================