A Genetic Basis for Stress-Neuroendocrine-Immune Interactions

压力-神经内分泌-免疫相互作用的遗传基础

• 批准号: 8531143
• 负责人: ROBERT H. BONNEAU
• 金额: $ 18.58万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531143
• 关键词: 6q24-q25; Acute; Adult; Affect; African American; Alleles; American; Amino Acid Substitution; Amino Acids; Analgesics; Asparagine; Aspartic Acid; Behavioral; Biochemical; Child; Chromosomes; Chronic; Chronic stress; Communicable Diseases; Corticosterone; Cytotoxic T-Lymphocytes; Data; Development; Disease; Drug Addiction; Endocrine system; Epitopes; Ethnic Origin; European; Exhibits; Exons; Feeling; Foundations; Frequencies; Genes; Genetic; Genetic Polymorphism; Health; Herpesvirus 1; Heterozygote; Homozygote; Hormones; Human; Hydrocortisone; Immune; Immune response; Immune system; Immunity; Individual; Intervention; Japanese Population; Knowledge; Longevity; Longitudinal Studies; Measurement; Mediator of activation protein; Modeling; Molecular; Morphine Receptors; Mouse Strains; Mus; Natural Immunity; Nervous system structure; Neurosecretory Systems; Nucleotides; Opioid; Opioid Receptor; Pain; Personal Satisfaction; Phenotype; Plant Roots; Play; Predisposition; Production; Psychological Stress; Race; Receptor Gene; Research; Research Personnel; Resistance; Role; Scientist; Simplexvirus; Single Nucleotide Polymorphism; Stress; Testing; Time; Vaccination; Variant; Virus Diseases; acute stress; adaptive immunity; base; design; experience; human subject; hypothalamic-pituitary-adrenal axis; immune function; in vivo; interest; neuroimmunology; novel; pathogen; pathogen exposure; peptide hormone; psychologic; response; stressor; therapy design

DESCRIPTION (provided by applicant): Although the immune system was once thought to function autonomously, there is now compelling evidence that psychological stress-induced, neuroendocrine-derived peptides and hormones play a key role in regulating numerous aspects of immunity. Activation of the hypothalamic-pituitary-adrenal (HPA) axis and the production of corticosterone/cortisol is a major mediator of stress-induced effects on immune function and is modulated, in part, by the ¿ opioid receptor. However, the genetic factors which regulate HPA axis activity have not yet been elucidated. A relatively common single nucleotide functional polymorphism (SNP) has recently been identified in the human ¿ opioid receptor gene (OPRM1; A118G nucleotide exchange; asparagine-to-aspartic acid change at amino acid residue 40). Interestingly, the distribution of this SNP is closely aligned along specific races and ethnicities and its presence has recently been associated with increased sensitivity to pain and a reduced analgesic response to opioids. In addition, individuals having at least one copy of this A118G allele exhibit increased basal levels of cortisol and a decreased cortisol response to a behavioral stressor. How these alterations in the levels of cortisol affect immunity to infectious pathogens and the development of protective immunity in response to vaccinations remains to be determined. The studies described herein combine the interests and expertise of a basic scientist with research roots in stress-associated neuroimmunology and a clinician-scientist with interest and expertise in genetic-stress interactions, to test the hypothesis that the A118G polymorphism alters the HPA axis response to acute and chronic psychological stress which, in turn, affects the magnitude of the cytotoxic T lymphocyte (CTL)-based adaptive immune response to herpes simplex virus (HSV) infection. These studies will utilize a murine model of stress and measurements of HSV-specific immunity with which these investigators have considerable experience. Such studies will provide a foundation for longer-term studies to determine the impact of this A118G SNP on the human neuroendocrine response to stress, innate and adaptive immunity, resistance to infectious pathogens, and the ability to respond to vaccinations. The results from these studies may, in turn, promote the utilization of interventional strategies to minimize the levels of stress in individuals who harbor at least one copy of the A118G allele and who may not be able to effectively verbalize their feelings of psychological and physical stress and their need for stress-reduction intervention.

描述（由适用提供）：尽管曾经认为免疫系统可以自主发挥作用，但现在有令人信服的证据表明，心理压力引起的神经内分泌衍生的肽和马匹在确定免疫组织化学的许多方面都起着关键作用。下丘脑 - 垂体 - 肾上腺（HPA）轴的激活和皮质酮/皮质醇的产生是应激诱导的对免疫功能作用的主要介体，并部分由«阿片类​​受体调节。但是，调节HPA轴活性的遗传因素尚未阐明。最近已经在人类的阿片类受体基因（OPRM1; A118G核苷酸交换；在氨基酸住所中的天冬氨酸到天冬氨酸变化）中鉴定出了相对常见的单核苷酸功能多态性（SNP）。有趣的是，该SNP的分布与特定种族和种族密切相符 它的存在最近与对疼痛的敏感性增加以及对阿片类药物的镇痛反应降低有关。此外，该A118G等位基因至少具有一份副本的个体表现出增加的皮质醇基本水平和对行为应激源的皮质醇反应减少。皮质醇水平的这些改变如何影响免疫原分以及受保护的免疫原子的发展以及对疫苗接种的受保护免疫学的发展尚待确定。研究描述了基础科学家的兴趣和专业知识，其研究根源与压力相关的神经免疫性和具有兴趣和专业知识的临床科学家在遗传压力相互作用中，以检验A118G多态性的假设，即A118G多态性改变了HPA轴对急性和慢性心理压力的反应，从而影响了巨大的症状。 （CTL）基于对单纯疱疹病毒（HSV）感染的自适应免疫响应。这些研究将利用这些研究者具有丰富经验的HSV特异性免疫学测量的鼠模型。此类研究将为长期研究提供基础，以确定该A118G SNP对人类神经内分泌对压力，先天和适应性免疫学的反应，对感染性病原体的抗性以及对疫苗接种反应能力的影响。这些研究的结果可能又可以促进介入介入策略的利用，以最大程度地减少携带A118G等位基因至少一份副本的个人的压力水平，并可能无法有效地言辞其心理和身体压力的感觉，并需要减轻压力减轻压力。