Mechanisms Leading to Adrenal Zonation

描述（由申请人提供）：本申请是根据NIH通知提交的：NOT-OD-09-058 NIH宣布竞争性修订申请的恢复法案资金可用性。母体申请，“导致肾上腺带状化的机制”，最后通过NIDDK作为R01资助。在此，我们请求资金支持一个新的特定目标，这将使我们能够将肾上腺带化的研究扩展到转基因小鼠模型中。人的肾上腺皮质可以分为不同的区域，这些区域在形态和生化上都有差异。肾小球带醛固酮和束状带皮质醇的产生可以追溯到参与类固醇生物合成的酶的区域特异性表达。引起类固醇生成酶区域表达的机制尚未明确。在亲本R01研究中，我们提出验证肾上腺细胞中类固醇生成酶的表达是由肾小球和束状组织中核激素受体的相反活性引起的这一假说。在与这笔拨款相关的资助期内，我们在定义控制肾上腺带化的分子机制方面取得了相当大的进展，但就其性质而言，体外分析需要在体内得到证实。自该应用获得资助以来，我们已经成功地利用Cyp11B2启动子选择性靶向小鼠肾上腺肾小球。这现在提供了一个独特的机会，将我们过去研究的体外实验扩展到小鼠肾上腺。在这个竞争性补充中，我们提出了一个特定的目标，重点是开发一种转基因小鼠，允许选择性操纵肾上腺肾小球基因。在拟议的研究中，这种转基因小鼠将用于确定导致肾上腺带化的细胞谱系。总之，我们最近成功靶向小鼠肾上腺肾小球使我们能够提出一个新的特异性目标，这将：1)大大提高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，这将作为许多肾上腺研究人员的资源。这项修订的经费也将通过设立一个新的研究生职位和在完成研究目标所需的设备、用品和服务上的支出来刺激经济。

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.