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: 10292709
• 负责人: KARL J CLARK
• 金额: $ 1.43万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292709
• 关键词: Animal Model; Behavior; Corticosterone; Development; Disease; Environment; Genes; Genetic; Genetic Models; Genetic Transcription; Genomics; Glucocorticoid Receptor; Glucocorticoids; Health; Hydrocortisone; Link; Mental disorders; Mineralocorticoid Receptor; Modeling; Neurosecretory Systems; Onset of illness; Organism; Outcome; Pathway interactions; Play; Property; Regulation; Resources; Role; Signal Pathway; Signal Transduction; Stress; Stress Response Signaling; System; Vertebrates; Zebrafish; acute stress; biological adaptation to stress; follow-up; gene product; mutant; neuropsychiatric disorder; non-genomic; novel; novel diagnostics; novel therapeutics; receptor; response; 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.

抽象的 强烈的急性应力或长时间的压力使人体的压力反应（SR）系统不利 对生物体的健康，并与广泛的健康成果的发作或加重有关， 包括精神疾病。为了制定有效的压力疾病的治疗策略，这是 促进我们对调节身体反应的途径和基因的理解至关重要 压力。普遍的想法是，糖皮质激素（如皮质醇或皮质酮）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， 影响转录。然而，欣赏糖皮质激素在快速非基因组中扮演的角色 反应导致了人们的推动，以更好地了解这些非基因组反应如何导致压力 反应，整体压力系统调节以及对健康和疾病的贡献。识别和学习 调节或修改快速，非基因组压力反应的基因产品将显着影响我们对 SR法规如何有助于健康，有可能提供新的诊断和疗法，以防止或 治疗疾病。斑马鱼是具有配置的SR信号通路的遗传牵引脊椎动物 - A 属性的组合，使它们成为发现脊椎动物的遗传修饰剂的理想模型 特定的SR信号。在此提案中，我们打算阐明SR信号的关键调节器的贡献， 查看它们在快速非基因组信号传导中的作用，以及它们影响发展的潜力 脊椎动物中的SR。我们还将跟进发现与快速压力响应相关的新基因 行为并使用斑马鱼突变体的独特资源来发现影响脊椎动物的更多基因 Sr。