Mitochondrial regulation of stress reactivity in humans

人类应激反应的线粒体调节

基本信息

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
项目类别：
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

项目摘要

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表现为系统性的稳态负荷（AL）和异常应激反应特征，这是增加未来疾病风险的精神病理状况的特征。但个体间压力调节和反应性差异的生物学基础仍然存在未知。即使在暴露于标准化实验室挑战的健康个体群体中，作为特里尔社会压力测试（TSST），多个群体的反应程度存在显着差异生理系统，包括但不限于下丘脑-垂体-肾上腺（HPA）轴、自主神经系统神经系统 (ANS) 和心血管系统、代谢变化以及免疫和促炎症系统。所有压力系统的一个共同因素是它们对能源供应的依赖，能源供应为每一个压力系统提供燃料。应激反应的各个方面，包括分子、细胞、系统和认知/心理功能。在在细胞水平上，能量由线粒体提供，线粒体是细胞质中的独特细胞器，含有自己的基因组，即线粒体 DNA (mtDNA)，这对线粒体健康至关重要。线粒体DNA 缺陷导致线粒体结构和功能多个方面的失调，称为线粒体稳态负荷（MAL）。三个主要证据表明 MAL 有助于 AL 并调节压力人类的反应：i) 我们最近发现线粒体 DNA 在心理压力后释放人类 (PNEC 2019)，ii) 实验诱导的动物 MAL 引起多系统的特定改变对心理压力的生理反应（PNAS 2015），以及 iii) 线粒体是压力的来源激素，包括肾上腺线粒体中合成的皮质醇（Nat Genetics 2012）。总之，这些证据表明 MAL 可能会改变基线 AL 和应激反应性特征，为了解个体间压力调节和总体健康差异的根源提供了新的见解。在在这个项目中，我们对MAL、系统性AL、多系统应激反应性进行了首次全面评估对三组具有罕见遗传 mtDNA 缺陷的个体进行实验室挑战 (TSST) 在健康对照组中选择性地引起不同形式的 MAL。多系统应激生物标志物分析在禁食基线和应激反应条件下，将提供连接 MAL 的途径的全面测试强调人类的生理机能。生成的高维数据将使用综合数据进行处理分析方法和分类算法，包括交叉验证的机器学习模型，以识别对 MAL 有反应的静息和应激反应生物标志物特征。同时，对执行人员的评估心理社会功能的功能和关键领域，包括情绪、压力、焦虑、抑郁症状、和福祉将有助于提供新型线粒体心理生物学的全面了解途径。