Mitochondrial regulation of stress reactivity in humans

人类应激反应的线粒体调节

• 批准号: 10392915
• 负责人: Martin Picard
• 金额: $ 77.11万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392915
• 关键词: Adrenal Glands; Algorithms; Animals; Anxiety; Autonomic nervous system; Biological; Biological Markers; Biology; Blood; Blood Pressure; Brain; Cardiovascular system; Catecholamines; Cells; Chronic; Clinical; Clinical Data; Cognitive; Control Groups; Cytoplasm; Data; Data Analytics; Defect; Dependence; Disease; Disease Pathway; Energy Supply; Esthesia; Executive Dysfunction; Exhibits; Exposure to; Fasting; Fatigue; Foundations; Future; Galvanic Skin Response; Gatekeeping; Generations; Genetic; Genome; Glucocorticoids; Hair; Health; Heart; Hematology; Hormones; Hour; Human; Hydrocortisone; Hypothalamic structure; IL6 gene; Immune; Immune system; Individual; Individual Differences; Inflammatory; Inherited; Laboratories; Leukocytes; Link; Maintenance; Maps; Measures; Mental Depression; Metabolic; Methods; Mitochondria; Mitochondrial DNA; Molecular; Monitor; Moods; Mus; National Institute of Mental Health; Neuropsychology; Neurosecretory Systems; Organelles; Participant; Pathway interactions; Personal Satisfaction; Persons; Phenotype; Physiological; Physiology; Pituitary Gland; Ploidies; Population; Positioning Attribute; Process; Protocols documentation; Psychological Stress; Psychophysiology; Psychosocial Factor; Recovery; Regulation; Respiratory Chain; Rest; Role; Saliva; Signal Transduction; Source; Specificity; Standardization; Stress; Structure; System; Testing; Time; Translating; Trier Social Stress Test; allostatic load; base; biological adaptation to stress; biomarker signature; cognitive function; cytokine; depressive symptoms; disorder risk; epigenome; executive function; experience; heart rate variability; hypothalamic-pituitary-adrenal axis; indexing; insight; instrument; machine learning model; mouse model; multidimensional data; negative affect; negative mood; novel; personalized predictions; pre-clinical; preclinical study; psychobiologic; psychologic; psychosocial; resilience; respiratory; response; stress reactivity; trait; urinary

Chronic dysregulation of physiological systems manifests systemically as allostatic load (AL) and in abnormal stress reactivity profiles, which are features of psychopathological conditions that increase future disease risk. But the biological basis underlying inter-individual differences in stress regulation and reactivity remains unknown. Even among populations of healthy individuals exposed to standardized laboratory challenges, such as the Trier social stress test (TSST), there are substantial differences in the magnitude of responses in multiple physiological systems, including but not limited to the hypothalamic-pituitary-adrenal (HPA) axis, the autonomic nervous system (ANS) and cardiovascular system, metabolic changes, and immune and pro-inflammatory systems. One common factor to all stress systems is their dependence on energy supply, which fuels every aspect of the stress response including molecular, cellular, systemic and cognitive/psychological functioning. At the cellular level, energy is provided by mitochondria, unique organelles that populate the cell cytoplasm and contain their own genome, the mitochondrial DNA (mtDNA), that is essential to mitochondrial health. MtDNA defects cause dysregulation of multiple aspects of mitochondrial structure and function, known as mitochondrial allostatic load (MAL). Three main lines of evidence suggest that MAL contributes to AL and regulates stress responses in humans: i) we recently discovered that the mtDNA is released following psychological stress in humans (PNEC 2019), ii) experimentally-induced MAL in animals caused specific alterations in the multisystem physiological responses to psychological stress (PNAS 2015), and iii) mitochondria are the source of stress hormones, including cortisol that is synthesized in mitochondria within the adrenal glands (Nat Genetics 2012). Together, this evidence suggests that MAL may alter both baseline AL and stress reactivity profiles, potentially providing new insight into the source of interindividual differences in stress regulation and health in general. In this project, we perform the first comprehensive assessment of MAL, systemic AL, multisystem stress reactivity to a laboratory challenge (TSST) in three groups of individuals who have rare genetic mtDNA defects that selectively causes different forms of MAL and in a healthy control group. Multisystem stress biomarker profiling under fasting baseline and stress reactive conditions will provide a comprehensive test of pathways linking MAL to stress physiology in humans. The resulting high-dimensionality data will be treated using integrative data analytic approaches and classifying algorithms, including cross-validated machine learning models, to identify resting and stress-reactive biomarker signatures responsive to MAL. In parallel, assessments of executive function and key domains of psychosocial functioning including mood, stress, anxiety, depressive symptoms, and well-being will contribute to provide a comprehensive picture of novel mitochondrial psychobiological pathways.

生理系统的慢性失调在系统上表现为同性载荷（AL）和异常 压力反应性概况，这是增加未来疾病风险的精神病理状况的特征。 但是生物学基础在压力调节和反应性方面的个体间差异仍然存在 未知。即使在面临标准化实验室挑战的健康人群中， 作为Trier社会压力测试（TSST），多个响应的大小存在很大差异 生理系统，包括但不限于下丘脑 - 垂体 - 肾上腺（HPA）轴，自主神经 神经系统（ANS）和心血管系统，代谢变化以及免疫和促炎性 系统。所有压力系统的共同因素是它们对能源供应的依赖 压力反应的方面，包括分子，细胞，全身和认知/心理功能。在 细胞水平，通过线粒体提供的能量，填充细胞质的独特细胞器和 包含其自己的基因组，即线粒体DNA（mtDNA），这对于线粒体健康至关重要。 mtDNA 缺陷导致线粒体结构和功能多个方面的失调，称为线粒体 同性载荷（MAL）。三个主要证据表明，MAL有助于AL并调节压力 人类的回应：i）我们最近发现，mtDNA在心理压力下释放 人类（PNEC 2019），ii）动物实验诱导的MAL引起了多系统的特定变化 对心理压力的生理反应（PNAS 2015）和iii）线粒体是压力的来源 激素，包括在肾上腺内线粒体中合成的皮质醇（Nat Genetics 2012）。 这些证据共同表明，MAL可能会改变基线Al和应力反应性谱，并有可能 提供有关压力调节和健康方面个体差异来源的新见解。在 这个项目，我们对MAL，系统性AL，多系统应力反应性进行了首次全面评估 在三组具有罕见遗传mtDNA缺陷的个体的实验室挑战（TSST）中 选择性地引起不同形式的MAL和健康对照组。多系统压力生物标志物分析 在禁食基线和应力反应条件下，将对连接Mal的途径进行全面测试 强调人类的生理学。最终的高维数据将使用集成数据处理 分析方法和分类算法，包括交叉验证的机器学习模型，以识别 静止和压力反应性的生物标志物特征对MAL有反应。同时，对执行的评估 社会心理功能的功能和关键领域，包括情绪，压力，焦虑，抑郁症状， 幸福感将有助于提供新颖的线粒体心理生物学的全面图片 途径。