The acd mouse: a model for congenital adrenal hypoplasia

描述（由申请人提供）：功能性肾上腺皮质对生命至关重要，先天性肾上腺发育不全患者的早期死亡证明了这一点。常染色体隐性小鼠突变型肾上腺皮质发育不良（adrenocortical dysplasia, add）是研究肾上腺器官发生的一个很好的模型，它与人类小型成人先天性肾上腺发育不全有着惊人的相似之处。与人类患者类似，突变的多动症/多动症动物缺乏“肾上腺皮质X区”，并具有功能失调的确定区，大多数在出生后不久死亡。血清皮质酮水平低，ACTH水平显著升高，与原发性肾上腺缺陷一致。通过以下具体目标鉴定和表征add突变是本提案的重点：目标1。执行add突变动物的详细表征；目标2。小鼠8号染色体和Aim 3上acd位点的遗传和物理图谱的改进。克隆并鉴定acd基因。add基因的鉴定将是了解正常和异常肾上腺生长的重要一步。这些研究将为未来人类肾上腺异常发育的研究奠定基础，并可能导致先天性肾上腺功能不全患者的重要治疗应用。

DESCRIPTION (provided by applicant): A functional adrenal cortex is essential for life as evidenced by the early death of patients with congenital adrenal hypoplasia. The autosomal recessive mouse mutant adrenocortical dysplasia (acd) is a good model for the study of adrenal organogenesis and shares some striking similarities with miniature adult congenital adrenal hypoplasia in humans. Similar to human patients, mutant acd/acd animals lack an "adrenocortical X zone and possess a dysfunctional definitive zone, and the majority die shortly after birth. Serum corticosterone levels are low and ACTH levels are significantly elevated, consistent with a primary adrenal defect. The identification and characterization of the acd mutation via the following specific aims is the focus of this proposal: Aim 1. Perform a detailed characterization of acd mutant animals; Aim 2. Refinement of the genetic and physical map of the acd locus on mouse chromosome 8, and Aim 3. Clone and characterize the acd gene. The identification of the acd gene will be an important step in the understanding of both normal and abnormal adrenal growth. These studies will provide the groundwork for future investigations of abnormal adrenal development in humans and may lead to important therapeutic applications for humans with congenital adrenal insufficiency. The career development program outlined in this proposal will build on my prior research experience and will also provide for the development of new techniques, interaction with a new mentor, and additional didactic training in Developmental Biology and Bioinformatics. The educational climate at the University of Michigan is outstanding and will allow me to foster these new skills. Ultimately, through this additional training I will be poised to continue my long-term career goal of becoming an Independent Investigator.