Development and genetics of rapid neuroendocrine stress response

快速神经内分泌应激反应的发育和遗传学

• 批准号: 10397544
• 负责人: KARL J CLARK
• 金额: $ 34.19万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397544
• 关键词: Address; Adrenal Glands; Affect; Animal Model; Anxiety Disorders; Behavior; Behavioral; Behavioral Assay; Biological Assay; Cardiovascular Diseases; Cells; Clinic; Complement; Corticosteroid Receptors; Corticosterone; Corticotropin; Corticotropin Receptors; Development; Diabetes Mellitus; Disease; Environment; Fishes; Gastrointestinal Diseases; Gene-Modified; Genes; Genetic; Genetic Models; Genetic Screening; Genetic Transcription; Genomics; Glucocorticoid Receptor; Glucocorticoids; Goals; Health; Hydrocortisone; Hypothalamic structure; Immune System Diseases; Insertional Mutagenesis; Iowa; Kinetics; Knowledge; Laboratories; Larva; Lead; Libraries; Light; Link; Mediating; Membrane; Mental disorders; Metabolic Diseases; Mineralocorticoid Receptor; Modeling; Molecular; Mood Disorders; Mutation; Nature; Neurosecretory Systems; Onset of illness; Organism; Orthologous Gene; Osmoregulation; Outcome; Pathway interactions; Physiology; Pituitary-Adrenal System; Play; Predisposition; Premature aging syndrome; Production; Property; Regulation; Resources; Rodent Model; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Stress; Stress Response Signaling; System; Systems Biology; Technology; Testing; Therapeutic; Universities; Vertebrates; Weight Gain; Zebrafish; acute stress; addiction; behavioral response; biological adaptation to stress; biological systems; conditional mutant; follow-up; gene product; human model; insight; mutant; neuropsychiatric disorder; non-genomic; novel; novel diagnostics; novel therapeutics; rapid testing; receptor; response; screening; skin disorder; stress reduction; stressor; therapeutic target; therapeutically effective

Abstract Intense acute stress or prolonged stress that overwhelms the body's stress response (SR) system is detrimental to an organism's health and associated with the onset or aggravation of a broad spectrum of health outcomes, including psychiatric disorders. To devise effective therapeutic strategies for stress-aggravated disorders, it is essential to advance our understanding regarding the pathways and genes that regulate our body's response to stress. The prevailing thought is that glucocorticoids, like cortisol or corticosterone, primarily act through genomic actions of their cognate receptors, mineralocorticoid (MR) and glucocorticoid receptors (GR), by effecting transcription. However, appreciation of the role glucocorticoids play in rapid non-genomic responses has led to a push to better understand how these non-genomic responses contribute to stress responses, overall stress system regulation, and contributions to health and disease. Identifying and studying gene products that regulate or modify rapid, non-genomic stress responses will significantly impact our understanding of how SR regulation contributes to health, potentially providing new diagnostics and therapeutics to protect against or treat disease. Zebrafish are genetically tractable vertebrates with conserved SR signaling pathways–a combination of properties that make them an ideal model for discovering genetic modifiers of vertebrate- specific SR signaling. In this proposal we intend to clarify the contribution of key regulators of SR signaling, looking at their role in rapid non-genomic signaling as well as their potential to influence development of the SR in vertebrates. We will also follow up on the discovery of novel genes linked to rapid stress responsive behaviors and use a unique resource of zebrafish mutants to discover more genes that influence the vertebrate SR.

摘要 严重的急性压力或长期的压力，使身体的应激反应系统不堪重负，这是有害的 与生物体的健康有关，并与一系列健康后果的出现或加重有关， 包括精神障碍。为了制定有效的治疗压力加重障碍的策略，它是 对促进我们对调节身体反应的途径和基因的理解是必不可少的 来施加压力。普遍认为，糖皮质激素，如皮质醇或皮质酮，主要通过 他们的同源受体，盐皮质激素(MR)和糖皮质激素受体(GR)的基因组作用，通过 影响转录的。然而，对糖皮质激素在快速非基因组中所起作用的认识 这些反应促使人们更好地了解这些非基因组反应是如何导致压力的 反应，整体压力系统调节，以及对健康和疾病的贡献。辨别和研究 调节或改变快速、非基因组应激反应的基因产物将显著影响我们对 SR监管如何有助于健康，可能提供新的诊断和治疗方法来预防或 治病。斑马鱼是基因易驯化的脊椎动物，具有保守的SR信号通路-a 这些特性的结合使它们成为发现脊椎动物遗传修饰物的理想模型- 特定的SR信令。在这项提案中，我们打算澄清SR信令的关键调节器的作用， 观察它们在快速非基因组信号传递中的作用以及它们影响 脊椎动物中的SR。我们还将跟进与快速应激反应有关的新基因的发现 并使用斑马鱼突变体的独特资源来发现更多影响脊椎动物的基因 高级