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: 7984158
• 负责人: SHAILAJA K MANI
• 金额: $ 33.55万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-23 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7984158
• 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. PUBLIC HEALTH RELEVANCE: The proposed studies will attempt to provide an integrated model of progesterone action in physiology and behavior. Identification of novel mechanisms of signal transduction by progesterone and the molecular events leading to its interactions with the intracellular PRs will contribute to a better understanding of P's role in several pathological conditions including depression, anxiety disorders, pre menstrual syndrome, breast cancer, endometriosis and uterine fibroids.

描述(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，导致各种物种的生理和生殖行为的变化。P在大脑中的作用主要是通过经典的细胞内孕激素受体(PR)调节靶基因表达的“经典”基因组机制来实现的。越来越多的证据表明，P效应还通过“非经典”途径诱导蛋白激酶介导的核外和细胞内信号转导通路的快速激活。同样明显的是，这些快速信号事件与经典的PR介导的机制“串扰”，以调节P的作用。然而，介导快速效应和串扰的受体机制还不是很清楚。我们已经报道了在P敏感的脑区，由P启动的蛋白激酶、PKA、PKC和CaMKII的快速激活。初步数据表明，P的这种快速信号转导激活了G蛋白和随后的下游细胞质信号分子。我们推测，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提高与经典PR的串扰水平，通过支架蛋白促进神经细胞内调节大脑和行为的水平。这项建议侧重于确定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中P敏感区域快速P激活信号通路(S)潜在的生化和分子事件。具体目标1将在体外确定G蛋白快速激活P的机制及其下游信号通路。具体目标2将检查G蛋白介导的机制在P介导的信号和行为中的体内功能相关性。具体目标3将验证这样的假设，即支架蛋白将大脑和行为中快速的核外信号通路与细胞内PR介导的基因组通路整合在一起。 公共卫生相关性：拟议的研究将试图提供黄体酮在生理和行为中作用的综合模型。识别孕酮信号转导的新机制及其与细胞内PR相互作用的分子事件将有助于更好地理解P在抑郁症、焦虑症、经前综合征、乳腺癌、子宫内膜异位症和子宫肌瘤等病理疾病中的作用。