Mechanisms Leading to Adrenal Zonation

描述(由申请人提供)：此申请是对NIH通知的回应：NOT-OD-09-058 NIH宣布可为竞争性修订申请提供恢复法案资金。上级申请，“导致肾上腺分区的机制”，上一次通过NIDDK作为R01赠款获得资助。在此，我们请求资金支持一个新的具体目标，使我们能够将我们对肾上腺分区的研究扩展到转基因小鼠模型。人的肾上腺皮质可以划分为不同的区域，这些区域在形态和生化上都有差异。球状带中的醛固酮和束状带中的皮质醇的产生可以追溯到参与类固醇生物合成的酶的区带特异性表达。导致类固醇合成酶的区带性表达的机制尚未确定。在母公司R01的资助中，我们建议检验肾上腺细胞类固醇合成酶的表达是由于肾小球和束状核中的核激素受体的相反活动所致的总体假设。在与这笔赠款相关的资助期内，我们在确定控制肾上腺分区的分子机制方面取得了相当大的进展，但根据其性质，体外分析需要在体内得到证实。自从这项应用获得资助以来，我们已经成功地利用Cyp11B2启动子选择性地靶向了小鼠肾上腺小球。这为我们将过去研究的体外实验扩展到小鼠肾上腺提供了独特的机会。在这份竞争性补充材料中，我们提出了一个特定的目标，即专注于开发一种转基因小鼠，使其能够选择性地操纵肾上腺小球基因。在拟议的研究中，这只转基因小鼠将被用来确定导致肾上腺分区的细胞谱系。总而言之，我们最近针对小鼠肾上腺肾小球的成功靶向使我们能够提出一个新的具体目标：1)极大地增强父母资助的拟议研究的意义；2)允许开发一种新的小鼠模型，作为许多肾上腺研究人员的资源。这一修订的资金还将通过设立一个新的研究生职位以及用于实现研究目标所需的设备、用品和服务的支出，作为经济刺激。 公共卫生相关性：拟议的研究将导致开发一种新的转基因小鼠模型，该模型将成为推进肾上腺研究的有效、不可或缺的工具。在这里，我们将使用这个新的小鼠模型来定义肾上腺皮质区域的细胞谱系。未来的研究将能够使用这个模型来更好地确定导致肾上腺疾病的机制。

DESCRIPTION (provided by applicant): This application is being submitted in response to the NIH Notice: NOT-OD-09-058 NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. The parent application, "Mechanisms Leading to Adrenal Zonation", was last funded as an R01 grant through the NIDDK. Herein, we request funding to support a new specific aim that will allow us to extend our studies on adrenal zonation into transgenic mouse models. The human adrenal cortex can be divided into distinct zones that have both morphologic and biochemical differences. The production of aldosterone in the zona glomerulosa and cortisol in the zona fasciculata can be traced to the zone-specific expression of the enzymes involved in steroid biosynthesis. The mechanisms causing zonal expression of the steroidogenic enzymes have not been defined. In the parent R01 grant, we proposed to test the overall hypothesis that adrenal cell expression of steroidogenic enzymes results from the opposing activities of nuclear hormone receptors in the glomerulosa and fasciculata. Over the funding periods associated with this grant, we have made considerable progress in defining the molecular mechanisms controlling adrenal zonation but, by its nature, in vitro analyses require confirmation in vivo. Since the funding of this application, we have succeeded in selectively targeting the mouse adrenal glomerulosa using the Cyp11B2 promoter. This now provides the unique opportunity to expand the in vitro experiments of our past studies into the mouse adrenal. In this competitive supplement, we propose one Specific Aim that focuses on the development of a transgenic mouse that will allow the selective manipulation of adrenal glomerulosa genes. In the proposed studies this transgenic mouse will be used to determine the cell lineage leading to adrenal zonation. In summary, our recent successful targeting of the mouse adrenal glomerulosa has allowed us to propose a new Specific Aim that will: 1) greatly enhance the significance of the parent grant's proposed research, and 2) allow the development of a new mouse model that will act as a resource for many adrenal researchers. The funding of this revision will also act as an economic stimulus through the creation of a new graduate student position and spending on equipment, supplies and services needed to accomplish the research goals. PUBLIC HEALTH RELEVANCE: The proposed studies will lead to the development of a novel transgenic mouse model that will become an effective, indispensable tool to advance adrenal research. Herein, we will use this new mouse model to define the cell lineage for the zones of the adrenal cortex. Future studies will be able to use this model to better define the mechanisms leading to adrenal disease.