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。在产前，胎儿皮质区大量生长，在出生后，胎儿皮质消失，最终发育成成人皮质。肾上腺个体发生是器官发育的一种模式，涉及细胞生长和分化、细胞迁移和凋亡等多种生物学机制。我们的首要假设是，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。我们进一步假设先天性肾上腺异常可能是由这些发育途径中的特定缺陷引起的。因此，我们提出的广泛目标是确定在产前和产后期间参与肾上腺皮质发育的基因，并表征它们的结构和功能相互作用。为了实现这一目标，我们将追求以下具体目标：(1)识别和表征肾上腺皮质发育过程中差异表达的基因，包括那些参与(a)胎儿肾上腺皮质发育的基因；(b)产后从胎儿皮质向成人皮质过渡。(2)描述DAX1的发育功能，该基因在发生突变时可导致先天性肾上腺发育不全（AHC），包括(a) DAX1伴发者；(b) DAX1蛋白的结构与功能关系。这些研究结果将提高我们对正常肾上腺皮质个体发生的分子机制的理解。此外，我们将阐明机制和确定候选基因的病理过程，如肾上腺皮质发育不全，发育不全和肿瘤发生。

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.