The acd mouse: a model for congenital adrenal hypoplasia

描述(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良患者的早期死亡证明了这一点。常染色体隐性遗传性小鼠肾上腺皮质发育不良(ACD)是研究肾上腺器官发生的良好模型，与人类微型成人先天性肾上腺发育不良有显著的相似性。与人类患者相似，突变的ACD/ACD动物缺乏“肾上腺皮质X区”，并拥有一个功能失调的终止区，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相一致。通过以下特定目的鉴定和鉴定ACD突变是本建议的重点：目的1.对ACD突变动物进行详细的鉴定；目的2.完善小鼠8号染色体上ACD基因座的遗传和物理图谱；以及目的3.克隆和鉴定ACD基因。ACD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发育异常的研究提供基础，并可能导致对患有先天性肾上腺功能不全的人类的重要治疗应用。 本提案中概述的职业发展计划将建立在我以前的研究经验的基础上，还将提供新技术的开发、与新导师的互动以及发育生物学和生物信息学的额外教学培训。密歇根大学的教育氛围非常好，能让我培养这些新技能。最终，通过这次额外的培训，我将准备好继续我成为一名独立调查员的长期职业目标。

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.