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时间的压力会压垮身体的压力反应（SR）系统，这是有害的 对生物体健康的影响，并与广泛的健康结果的发生或恶化相关， 包括精神疾病为了设计有效的治疗策略，压力加重障碍，它是 这对我们进一步了解调节我们身体反应的途径和基因至关重要 压力流行的观点是糖皮质激素，如皮质醇或皮质酮，主要通过 其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， 实现转录。然而，对糖皮质激素在快速非基因组化中所起作用的认识， 这些非基因组反应导致了更好地理解这些非基因组反应如何导致压力的推动 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 调节或改变快速的非基因组应激反应的基因产物将显著影响我们对 SR法规如何有助于健康，可能提供新的诊断和治疗方法，以防止或 治疗疾病。斑马鱼是一种遗传学上易于控制的脊椎动物，具有保守的SR信号通路， 这些特性的组合使它们成为发现脊椎动物遗传修饰剂的理想模型- 特定的SR信令。在这个提案中，我们打算澄清SR信号的关键调节器的贡献， 研究它们在快速非基因组信号传导中的作用以及它们影响细胞发育的潜力， 脊椎动物中的SR。我们还将跟踪发现与快速应激反应有关的新基因。 行为，并利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。 Sr.