Non-Classical Cellular Pathways for Progesterone Regulation of Behavior

黄体酮行为调节的非经典细胞途径

基本信息

批准号：
8644973
负责人：
SHAILAJA K MANI
金额：
$ 5.64万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-08 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8644973
关键词：
Affect Antisense Oligonucleotides Anxiety Disorders Area Behavior Behavioral Biochemical Brain Brain region CREB1 gene Cell physiology Cells Co-Immunoprecipitations Coupled Coupling Cyclic AMP-Dependent Protein Kinases Cytoplasm Data Estradiol Estrus Event Female GTP-Binding Proteins Gene Expression Genomics Goals Hormonal Hypothalamic structure In Vitro Laboratories Lordosis MAP Kinase Gene Mediating Membrane Mental Depression Modeling Molecular Neuraxis Neurons Neurosecretory Systems Ovarian Steroid Hormone Pathway interactions Phosphotransferases Physiology Pituitary Gonadotropins Play Population Preparation Progesterone Progesterone Receptors Protein Kinase Proteins Rattus Regulation Reporting Reproduction Reproductive Behavior Role Scaffolding Protein Signal Pathway Signal Transduction Signaling Molecule Steroid Receptors Syndrome Testing Tissues Uterine Fibroids Vertebrates adapter protein brain behavior calmodulin-dependent protein kinase II endometriosis in vivo knock-down malignant breast neoplasm novel protein activation protein kinase A kinase public health relevance receptor response scaffold

项目摘要

DESCRIPTION (provided by applicant): The ovarian steroid hormones, estradiol and progesterone, regulate cellular functions in the central nervous system resulting in changes in physiology and reproductive behavior in a variety of species. P effects in the brain are primarily mediated through the "classical" genomic mechanism of action via classical intracellular progestin receptors (PRs) to modulate target gene expression. Increasing evidence suggests that P effects are also mediated via "non-classical" pathways to induce rapid activation of protein kinase-mediated extranuclear, intracellular signal transduction cascades. It is also becoming apparent that these rapid signaling events "cross talk" with the classical PR-mediated mechanisms to mediate P action. However, the receptor mechanisms mediating the rapid effects and cross talk are not well understood. We have reported P-initiated rapid activation of kinases, PKA, PKC and CaMKII in P sensitive regions of the brain. Preliminary data suggest that this rapid signaling by P activates G proteins and subsequent downstream cytoplasmic signaling molecules. We hypothesize that these rapid effects could be mediated by novel membrane receptors. The signal amplification achieved by these cascades could enhance the level of cross talk with classical PRs, facilitated by scaffolding proteins, within the neuronal cells to regulate brain and behavior. This proposal focuses on the determination of the "non-classical" mechanisms of P action that extend beyond the classical intracellular steroid receptor- mediated pathways. In particular, we propose to determine the biochemical and molecular events underlying the rapid P- activated signaling pathway(s) in P-sensitive areas of the rat brain. Specific aim 1 will identify the mechanism underlying the rapid P activation of G proteins and the downstream signaling pathways in vitro. Specific aim 2 will examine the in vivo functional relevance of G protein-mediated mechanisms in P- mediated signaling and behavior. Specific aim 3 will test the hypothesis that a scaffolding protein integrates the rapid extranuclear signaling pathways with the intracellular PR-mediated genomic pathway in brain and behavior.

描述（由申请人提供）：卵巢类固醇激素、雌二醇和黄体酮调节中枢神经系统的细胞功能，导致多种物种的生理和生殖行为发生变化。大脑中的 P 效应主要通过“经典”基因组作用机制介导，通过经典的细胞内孕激素受体 (PR) 来调节靶基因表达。越来越多的证据表明，P 效应也通过“非经典”途径介导，诱导蛋白激酶介导的核外、细胞内信号转导级联的快速激活。越来越明显的是，这些快速信号传导事件与经典的 PR 介导机制“串扰”以介导 P 作用。然而，介导快速效应和串扰的受体机制尚不清楚。我们报道了 P 引发的大脑 P 敏感区域激酶、PKA、PKC 和 CaMKII 的快速激活。初步数据表明，P 的这种快速信号传导会激活 G 蛋白和随后的下游细胞质信号分子。我们假设这些快速效应可能是由新型膜受体介导的。这些级联实现的信号放大可以增强神经元细胞内与经典 PR 的串扰水平，通过支架蛋白促进，从而调节大脑和行为。该提案的重点是确定 P 作用的“非经典”机制，该机制超出了经典的细胞内类固醇受体介导的途径。特别是，我们建议确定大鼠大脑 P 敏感区域中快速 P 激活信号通路背后的生化和分子事件。具体目标 1 将确定 G 蛋白快速 P 激活的机制以及体外下游信号通路。具体目标 2 将检查 G 蛋白介导的机制在 P 介导的信号传导和行为中的体内功能相关性。具体目标 3 将检验支架蛋白将快速核外信号传导途径与大脑和行为中细胞内 PR 介导的基因组途径整合的假设。