PROOPIOMELANOCORTIN DEVELOPMENT AND REGULATION OF THE STRESS RESPONSE

原黑皮质素的发育和应激反应的调节

• 批准号: 5212838
• 负责人: MALCOLM James LOW
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5212838
• 关键词: cell differentiation; embryonic stem cell; endorphins; gene mutation; genetic manipulation; genetically modified animals; hormone regulation /control mechanism; laboratory mouse; neuroendocrine system; proopiomelanocortin; stress; tissue mosaicism

Acute and chronic stress produce a characteristic array of metabolic, endocrine, and behavioral changes in the mammal. Among these changes are increased secretion of glucocorticoid hormones from the adrenal glands, an inhibition of reproductive function, and a form of endogenous opiate mediated analgesia. In the human numerous disorders including depression, anorexia, alcoholism and chronic diseases are associated with these stress responses. A family of neuropeptides including adrenocorticotrophic hormone (ACTH), alpha melanocyte stimulating hormone (alphaMSH), and beta-endorphin derived from the precursor protein proopiomelanocortin (POMC) are essential chemical mediators of the stress response. POMC is first produced in specialized neurons of the brain and in pituitary cells at critical points in development of the brain and endocrine glands suggesting that PMOC also plays an important role in regulating the growth and differentiation of these tissues. The goal of our project is to understand the physiological role of each of the peptides derived from POMC in the normal development of the neuroendocrine systems and in the regulation of the neuroendocrine responses to stress. To accomplish this goal, we will create loss of function mutations in the POMC gene by homologous recombination in embryonic stem cells and use these cells to subsequently generate chimeric transgenic mice by blastocyst injection. The resulting mice will carry mutant POMC alleles that either block the production of all functional POMC peptides or that result in a selective loss of beta- endorphin(1-31). Homozygous POMC gene mutated mice will be analyzed throughout prenatal development to characterize the effects on neuroendocrine cell proliferation and cytodifferentiation. These developmental studies will focus on the paraventricular and antero- ventral periventricular nuclei of the hypothalamus because they are nodal points of the central circuitry controlling the hypothalamic-pituitary- adrenal and hypothalamic-pituitary-gonadal axes, respectively. The beta- endorphin deficient mice are expected to survive into adulthood and will be used to determine the role of centrally produced beta-endorphin in the modulation of the hypothalamic-pituitary axis under basal and stress conditions and in the expression of stress-induced analgesia. In the future, our molecular genetic approach will also be applied to produce mice carrying POMC alleles mutated in such a way to prevent the production of alphaMSH or mutated alleles for specific POMC peptide receptor subtypes to prove the physiological function of each of these molecular components of the mammalian stress response.

急性和慢性应激会产生代谢的特征阵列 内分泌和哺乳动物的行为变化。 其中包括 增加肾上腺糖皮质激素的分泌， 抑制生殖功能和一种内生鸦片形式 介导的镇痛。 在人类中，包括 抑郁症，厌食症，酒精中毒和慢性疾病与 这些压力反应。 一个神经肽家族，包括 肾上腺皮质营养激素（ACTH），α黑素细胞刺激激素 （alphamsh）和β-内啡肽源自前体蛋白 proOpiomelanocortin（POMC）是应力的必不可少的化学介质 回复。 POMC首先是在大脑的专门神经元中产生的 在垂体细胞中，大脑发育的关键点 内分泌腺表明PMOC在 调节这些组织的生长和分化。 目标 我们的项目是了解每个项目的生理作用 源自POMC的肽在正常发育中 神经内分泌系统和神经内分泌的调节 对压力的反应。 为了实现这一目标，我们将造成损失 通过同源重组中POMC基因中的功能突变 胚胎干细胞，然后使用这些细胞来生成 嵌合转基因小鼠通过胚泡注射。 由此产生的小鼠 将携带突变的POMC等位基因，以阻止所有人的产生 功能性POMC肽或导致β-的选择性丧失 内啡肽（1-31）。 将分析纯合POMC基因突变小鼠 整个产前发育以表征对 神经内分泌细胞的增殖和细胞分化。 这些 发展研究将集中于室室和前室 下丘脑的腹侧脑室核，因为它们是淋巴结的 控制下丘脑 - 垂体 - 肾上腺和下丘脑 - 垂体 - 基达轴。 beta- 内啡肽缺乏小鼠预计将生存到成年，将会 用于确定中心产生的β-内啡肽在 基础和应力下的下丘脑垂体轴的调节 条件和压力诱导的镇痛的表达。 在 未来，我们的分子遗传方法也将应用于生产 携带POMC等位基因的小鼠以这种方式进行突变以防止 用于特定POMC肽的αSH或突变等位基因的产生 受体亚型证明每一种的生理功能 哺乳动物应激反应的分子成分。