Non-Classical Cellular Pathways for Progesterone Regulation of Behavior

黄体酮行为调节的非经典细胞途径

• 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
• 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

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，雌二醇和孕酮，调节中枢神经系统的细胞功能，导致多种物种生理和生殖行为的改变。脑中的P效应主要是通过经典的细胞内孕激素受体（PRs）调节靶基因表达的“经典”基因组作用机制介导的。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，这些快速信号事件与经典pr介导的机制“串扰”来介导P的作用。然而，介导快速效应和串扰的受体机制尚不清楚。我们已经报道了脑内P敏感区域中P启动的激酶、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激活了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的膜受体介导的。这些级联实现的信号放大可以提高与经典pr的串扰水平，由支架蛋白促进，在神经元细胞内调节大脑和行为。该建议侧重于确定P作用的“非经典”机制，这些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敏感区域快速P激活信号通路的生化和分子事件。特异性目的1将确定G蛋白快速P激活的机制和体外下游信号通路。特异性目标2将研究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。特异性目的3将验证一个支架蛋白在大脑和行为中整合了快速核外信号通路和细胞内pr介导的基因组通路的假设。