MOLECULAR MECHANISMS OF ADRENAL DEVELOPMENT

肾上腺的发育是复杂的，在分子水平上知之甚少。在出生前，胎儿皮质带大量生长，在出生后，胎儿皮质消失，最终的成人皮质发育。肾上腺个体发育是器官发育的模型，涉及细胞生长和分化、细胞迁移和细胞凋亡等多种生物学机制。我们的总体假设是，特定调控基因在肾上腺发育的关键阶段发挥着明确的作用，这些基因通过可识别的功能基序，在一个复杂的发育调控基因网络中相互作用。我们进一步假设，肾上腺的先天性异常可能是由这些发育途径中的特定缺陷引起的。因此，我们对该提案的广泛目标是在出生前和出生后确定与肾上腺皮质发育有关的基因，并表征它们的结构和功能相互作用。为了实现这一目标，我们将致力于以下具体目标：(1)鉴定和鉴定肾上腺皮质发育过程中差异表达的基因，包括与(A)胎儿肾上腺皮质发育有关的基因；(B)产后从胎儿肾上腺皮质向成人肾上腺皮质过渡的基因。(2)研究DAX1的发育功能，DAX1是肾上腺发育不全先天发育不良(AHC)的致病基因，其突变包括(A)与DAX1配对；(B)DAX1蛋白的结构和功能之间的关系。这些研究结果将提高我们对正常肾上腺皮质个体发育的分子机制的理解。此外，我们还将阐明发病机制并确定各种病理过程的候选基因，包括肾上腺皮质发育不全、发育不良和肿瘤发生。

Adrenal gland development is complex and poorly understood at the molecular level. In the prenatal period, there is massive growth of a fetal cortical zone, and in the postnatal period, the fetal cortex disappears and the definitive adult cortex develops. Adrenal ontogeny is a model for organ development, involving biological mechanisms as varied as cell growth and differentiation, cell migration and apoptosis. Our overarching hypothesis is that specifically regulated genes play definable roles at critical stages of adrenal development, and that these genes, through recognizable functional motifs, interact within a complex network of developmentally regulated genes. We further hypothesize that congenital abnormalities of adrenals may result from specific defects in these developmental pathways. Therefore, our broad objective for the proposal is to identify genes involved in adrenal cortical development, during the pre- and postnatal periods, and to characterize their structural and functional interactions. In order to achieve this objective, we will pursue the following Specific Aimes: (1) To identify and characterize genes differentially expressed during adrenal cortical development, including those involved in the (a) Development of the fetal adrenal cortex; and (b) Transition from fetal to adult cortex postpartum. (2) To characterize the developmental function of DAX1, the gene responsible, when mutated, for Adrenal Hypoplasia Congenita (AHC), including (a) Partners with DAX1; and (b) relationships between structure and function for the DAX1 protein. The results of these investigations will improve our understanding of the molecular mechanisms involved in normal adrenal cortical ontogeny. In addition, we will elucidate mechanisms and identify candidate genes for pathologic processes as varied as adrenal cortical aplasia, hypoplasia and tumorigenesis.