Genetic Analysis of the Role of Pro-opiomelanocortin Peptides in Mouse Adrenal Maintenance and Function

前阿片黑素皮质素原(POMC)是脊椎动物中高度保守的基因。它编码一种激素前体，由此产生一系列具有不同功能的小肽，包括促肾上腺皮质激素、黑素细胞刺激素和-内啡肽。研究人员产生了一种完全缺乏POMC多肽的小鼠突变体。虽然POMC缺失突变体出生时肾上腺形态正常，但他们的肾上腺表现出两个缺陷：第一，他们不释放糖皮质激素，他们产生的盐皮质激素水平降低；第二，他们随着年龄的增长而退化，最终在成年后缺乏。在这个项目中，研究人员将利用他们在整个动物中的小鼠模型，结合药理学和遗传学方法a)识别肾上腺维持和功能所需的特定POMC多肽或多肽组合，以及b)识别肾上腺中依赖POMC衍生信号调节其维持和功能的分子过程。该项目将通过促进发现和理解将研究和教育结合起来，同时在概念和实践上培训不同水平的学生从事科学事业。拟议的研究将扩大代表性不足群体的参与，特别是俄克拉荷马州地域代表性不足群体的参与。这项拟议的研究对科学的好处在于阐明了脊椎动物器官维持和功能的一般原则，这些经验教训将适用于许多其他生物系统。拟议中的研究对社会的好处在于促进知识和教育。

Pro-opiomelanocortin (POMC) is a gene highly conserved in vertebrates. It encodes for a pro-hormone from which a number of small peptides with a diverse array of functions is produced, including adrenocorticotropin, melanocyte stimulating hormone, and -endorphin. The investigators generated a mouse mutant which completely lacks all POMC peptides. While POMC null mutants are born with morphologically normal adrenal glands, their adrenals exhibit two defects: First, they do not release glucocorticoids, and they produce reduced levels of mineralocorticoids; and second, they regress with age and are eventually lacking in the adult. In this project the investigators will utilize their mouse model in a whole animal, combined pharmacological and genetic approach a) to identify the specific POMC peptide or peptide combination required for maintenance and function of the adrenals, and b) to identify the molecular processes in the adrenal mediating its maintenance and function that are dependent on POMC-derived signals. This project will integrate research and education by advancing discovery and understanding while at the same time training, both conceptually and practically, students at different levels in their scientific careers. The proposed research will broaden the participation of underrepresented groups, specifically of geographically underrepresented groups in the State of Oklahoma. The benefit of the proposed research to science lies in illuminating general principles of organ maintenance and function in vertebrate organisms, lessons which will be applicable to many other biological systems. The benefit of the proposed research to society lies in advancing knowledge and promoting education.