Impact of Sex on Prenatal Stress-Immune Programming of Depression and Autonomic Dysregulation

性别对抑郁症和自主神经失调的产前应激免疫编程的影响

基本信息

批准号：
10089493
负责人：
JILL M GOLDSTEIN
金额：
$ 56.29万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2020-02-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10089493
关键词：
Adrenal Glands Adult Age Amygdaloid structure Anterior Archives Area Arousal Attenuated Autonomic Dysfunction Baroreflex Biological Markers Blood Pressure Brain Cardiac Cardiovascular Diseases Coupled Cytokine Receptors Devices Early Intervention Electrocardiogram Female Fetal Development Follow-Up Studies Functional Magnetic Resonance Imaging Functional disorder Gene Expression Genes Genetic Glucocorticoid Receptor Glucocorticoids Gonadal Steroid Hormones Heart Heart Diseases Hippocampus (Brain)Homeostasis Hormones Human Hydrocortisone Hyperactivity Hypothalamic structure Immune Immune response Immunologic Markers Immunologic Tests Impairment Individual Inflammatory Innate Immune System Interleukin-1 beta Interleukin-6 Knowledge Life Longevity Major Depressive Disorder Measures Mediating Mental Depression Molecular Moods Mothers Myocardial Ischemia Natural Immunity Outcome Pathway interactions Peripheral Peripheral Blood Mononuclear Cell Physiological Physiology Pituitary Gland Prefrontal Cortex Pregnancy Public Health Recurrence Rest Risk Sex Differences Steroid Receptors Stress Structure TNF gene Testing Therapeutic Time Transcranial Doppler Ultrasonography Variant Woman base biological adaptation to stress brain abnormalities brain circuitry cingulate cortex cohort cytokine disability early detection biomarkers emerging adult fetal follow-up heart rate variability hypercortisolemia hypothalamic-pituitary-adrenal axis immune system function in vivo innovation men middle age mortality risk neurovascular neurovascular coupling novel novel therapeutics offspring prenatal prenatal exposure prenatal stress recruit response sex sexual dimorphism steroid hormone therapeutic development transcriptomics

Adrenal Glands Adult Age Amygdaloid structure Anterior Archives Area Arousal Attenuated Autonomic Dysfunction Baroreflex Biological Markers Blood Pressure Brain Cardiac Cardiovascular Diseases Coupled Cytokine Receptors Devices Early Intervention Electrocardiogram Female Fetal Development Follow-Up Studies Functional Magnetic Resonance Imaging Functional disorder Gene Expression Genes Genetic Glucocorticoid Receptor Glucocorticoids Gonadal Steroid Hormones Heart Heart Diseases Hippocampus (Brain)Homeostasis Hormones Human Hydrocortisone Hyperactivity Hypothalamic structure Immune Immune response Immunologic Markers Immunologic Tests Impairment Individual Inflammatory Innate Immune System Interleukin-1 beta Interleukin-6 Knowledge Life Longevity Major Depressive Disorder Measures Mediating Mental Depression Molecular Moods Mothers Myocardial Ischemia Natural Immunity Outcome Pathway interactions Peripheral Peripheral Blood Mononuclear Cell Physiological Physiology Pituitary Gland Prefrontal Cortex Pregnancy Public Health Recurrence Rest Risk Sex Differences Steroid Receptors Stress Structure TNF gene Testing Therapeutic Time Transcranial Doppler Ultrasonography Variant Woman base biological adaptation to stress brain abnormalities brain circuitry cingulate cortex cohort cytokine disability early detection biomarkers emerging adult fetal follow-up heart rate variability hypercortisolemia hypothalamic-pituitary-adrenal axis immune system function in vivo innovation men middle age mortality risk neurovascular neurovascular coupling novel novel therapeutics offspring prenatal prenatal exposure prenatal stress recruit response sex sexual dimorphism steroid hormone therapeutic development transcriptomics

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项目摘要

PROJECT 1 SUMMARY. Major depressive disorder (MDD) topped ischemic heart disease as the number one cause of disability worldwide, and women have twice the risk of men. Although this is well-known, even recent studies of brain circuitry and genes associated with mood dysregulation and MDD per se do not investigate sex effects nor incorporate even current sex-dependent knowledge into development of therapeutics. This is surprising since MDD is associated with abnormalities in stress response circuitry including hypothalamus (HYPO), amygdala (AMYG), hippocampus (HIPP), anterior cingulate cortex (ACC), and ventromedial and orbital prefrontal cortices (vmPFC, OFC), areas that are among the most sexually dimorphic in the brain. HIPP, HYPO, AMYG, and PFC are dense in sex steroid and glucocorticoid receptors coupled with cytokine receptors, in particular, TNF-α, IL-1β, IL-6, the major co-activators of the hypothalamic pituitary adrenal (HPA) axis. In fact, activity in these areas has been associated with cortisol response, autonomic dysfunction characterized by loss of parasympathetic cardiac tone, and immune responses, which we previously showed differed by sex. Furthermore, autonomic dysregulation is significantly associated with cardiovascular disease itself, with women at twice the risk of the co-occurrence of MDD and heart disease, leading to a 3-5-fold risk of death in women from heart disease, often with unrecognized and untreated MDD. This is a worldwide public health challenge, and thus understanding early biomarkers for the co-occurrence later in life will provide knowledge to intervene earlier. Leveraging a rare opportunity to investigate fetal antecedents to sex differences in adult MDD and associated impact on central and peripheral physiology in early midlife in human in vivo studies, we will test here that immune pathway abnormalities, beginning in fetal development, are associated with sex-dependent impacts on HYPO, HIPP, AMYG and PFC, resulting in lifelong recurrent MDD (rMDD), and dysregulation of hormone and immune responses to stress and autonomic dysfunction in early midlife. Adult subjects from our prenatal cohort, for whom prenatal sera are archived and who have been included in our follow-up studies for 60 years, will be re-recruited (80 cases with rMDD/50 healthy controls, equally divided by sex, now ages 55- 61) for the proposed study. We will test whether these prenatal immune biomarkers are associated with lifelong MDD and ANS and neurovascular dysregulation in early midlife (including structural and functional brain abnormalities in stress response circuitry, physiologic dysregulation) and neurovascular dysfunction. We predict that the sex differences in early midlife will be mediated by major depression in earlier adulthood, which we predict is associated with sex-selective dysregulation of innate immunity resulting from maternal prenatal exposure. Novel transcriptomic analyses of innate immunity genes will provide clues to immune pathways to sex differences in MDD and autonomic dysregulation. Our lifespan perspective is an innovative approach that will identify potential therapeutic sex-dependent targets for early intervention to attenuate disability later in life.

项目1摘要。重度抑郁症（MDD）以缺血性心脏病为第一全世界残疾的原因，女性的风险是男性的两倍。虽然这是众所周知的，甚至最近与情绪失调和MDD相关的脑电路和基因的研究本身不研究性别影响也不将当前的性别依赖性知识纳入理论的发展。这是令人惊讶的是，由于MDD与包括下丘脑的压力反应回路异常有关（hypo），杏仁核（杏仁核），海马（HIPP），前扣带回皮层（ACC）和腹侧和腹膜轨道前额叶皮层（VMPFC，OFC），是大脑中性二态性最大的区域。希普， Hypo，Amyg和PFC在性类固醇和糖皮质激素受体中均致密，结合细胞因子受体，特别是TNF-α，IL-1β，IL-6，是下丘脑垂体肾上腺（HPA）轴的主要共激活因子。事实，这些区域的活动与皮质醇反应，自主神经功能障碍有关通过失去副交感神经性心脏张力和免疫复杂，我们以前通过性别表现出不同的表现。此外，自主性失调与心血管疾病本身显着相关，女性以MDD和心脏病共呈现的风险的两倍，导致女性死亡的风险3-5倍从心脏病中，通常没有识别和未经治疗的MDD。这是全球公共卫生挑战，因此，在以后的生活中了解早期出现的早期生物标志物将提供干预的知识较早。利用一个难得的机会调查胎儿先例，以应对成人MDD的性别差异和在人体体内研究的早期中年对中央和周围生理学的相关影响，我们将测试在这里，从胎儿发育开始的免疫病变异常与性别依赖性有关对HYPO，HIPP，AMYG和PFC的影响，导致终身复发性MDD（RMDD），并失调中年早年对压力和自主神经功能障碍的马酮和免疫反应。我们的成人受试者产前血清的产前血清，并将其包括在我们的后续研究中 60岁将被重新申请（80例RMDD/50个健康对照的病例，同样由性别划分，现年55岁 - 61）用于拟议的研究。我们将测试这些产前免疫生物标志物是否与终身有关 MDD和ANS和ANS和神经血管失调早期（包括结构和功能性大脑压力反应回路，生理失调）和神经血管功能障碍的异常。我们预测中年早期的性别差异将由成年早期的重度抑郁症介导，我们预测，与母亲产前有关的先天免疫的性选择性失调有关接触。先天免疫学基因的新型转录组分析将为免疫途径提供线索 MDD和自主性失调的性别差异。我们的寿命观点是一种创新的方法将确定潜在的治疗性与性别依赖性靶标，以便早期干预以减轻以后的残疾。