Immune dysregulation by psychosocial distress

心理社会困扰导致的免疫失调

• 批准号: 8208149
• 负责人: Linda Janusek
• 金额: $ 53.12万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208149
• 关键词: Acetylation; Affect; American; Anxiety; Binding Sites; Biopsy; Breast; Cancer Control; Cancer Etiology; Cancer Patient; Cell Nucleus; Cell physiology; Cells; Cessation of life; Chromatin; DNA; DNA Binding; Development; Diagnosis; Distress; Epigenetic Process; Epithelial; Exhibits; Fright; Future; Gene Expression; Genes; Glucocorticoids; Growth; Histone Acetylation; Histones; Hydrocortisone; Immune; Immune System Diseases; Immune response; Immune system; Individual; Interferon Type II; Investigation; Lead; Link; Malignant Neoplasms; Mediating; Methodology; Modeling; Modification; Molecular; Mononuclear; Natural Killer Cells; Neoplasm Metastasis; Nervous system structure; Nuclear; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phosphorylation; Primary Neoplasm; Production; Promoter Regions; Psychoneuroimmunology; Recovery; Reporting; Repression; Risk; SECTM1 gene; Science; Staging; Stress; Symptoms; Technology; Testing; Time; Transcription Factor AP-1; Treatment/Psychosocial Effects; Uncertainty; Whole Blood; Woman; Work; base; biological adaptation to stress; breast cancer diagnosis; cancer diagnosis; chromatin immunoprecipitation; cohort; cytokine; design; disturbance in affect; emotional distress; experience; hypothalamic-pituitary-adrenal axis; immune function; insight; malignant breast neoplasm; novel strategies; perforin; peripheral blood; prospective; protective effect; psychobiologic; psychosocial; public health relevance; response; transcription factor; translational study; tumor; tumor growth; tumor initiation

DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer death in American women. It is no surprise that women respond to a diagnosis of breast cancer with substantial psychosocial distress. Evidence from psychoneuroimmunology demonstrates that psychosocial distress impairs immune function by reducing natural killer cell activity (NKCA) and the production of interferon (IFN) gamma. Both NKCA and IFN gamma contribute to protection from tumor initiation, primary tumor growth, and tumor metastasis. Of note, epithelial tumors, like those of the breast, are responsive to NK cells and IFN gamma; hence, reductions in these forms of immune defense are relevant to breast cancer. We show that women diagnosed with breast cancer experience psychosocial distress, which is accompanied by elevated levels of cortisol, decreased NKCA, and reduced IFN gamma production. The purpose of this project is to determine whether epigenetic pattern underlies the mechanism for the immune dysregulation that occurs with a diagnosis of breast cancer. Aim 1 will longitudinally assess women diagnosed with early stage breast cancer and evaluate the trajectory of their psychosocial, cortisol, and immune response with respect to their peripheral blood mononuclear (PBMC) epigenetic pattern. In Aims 2 and 3, these relationships will be investigated at the cellular and molecular level. Aim 2 will determine whether PBMC epigenetic pattern is associated with changes in the cellular levels of IFN gamma and/or perforin, two key effector molecules in cancer control. Aim 3 will determine whether PBMC epigenetic pattern is associated with changes in chromatin accessibility for the promoter regions of IFN gamma and/or perforin. Lastly, Aim 4 will evaluate an explanatory model that posits mediated relationships among the psychobiological variables. Latent growth curve analysis will be used to identify and evaluate the trajectories of the study variables with regard to PBMC epigenetic pattern. This project will provide a mechanistic understanding of immune dysregulation, consequent to psychosocial distress, and has the potential to spur development of new approaches to identify and manage individuals at risk for psychosocial distress mediated immune dysregulation. PUBLIC HEALTH RELEVANCE: Psychosocial distress is acknowledged to affect immune function relevant to cancer control but the molecular mechanism is unknown. One unexplored possibility is that epigenetic modifications result in immune dysfunction and an investigation of an epigenetic basis for immune-dysregulation in cancer patients will provide new insight into the effects of psychosocial-distress and will allow for future development of the means by which to manage this dysregulation.

描述（由申请人提供）：乳腺癌是美国女性癌症死亡的第二大原因。妇女应对严重的社会心理困扰的乳腺癌诊断就不足为奇了。心理肌免疫学的证据表明，心理社会遇险通过减少天然杀伤细胞活性（NKCA）和干扰素（IFN）伽玛的产生来损害免疫功能。 NKCA和IFN Gamma均有助于保护肿瘤启动，原发性肿瘤生长和肿瘤转移。值得注意的是，上皮肿瘤，例如乳房的肿瘤，对NK细胞和IFN伽玛有反应。因此，这些免疫防御形式的减少与乳腺癌有关。我们表明，被诊断出患有乳腺癌的妇女经历了心理困扰，伴随着皮质醇水平升高，NKCA降低并减少了IFN伽马产量。该项目的目的是确定表观遗传模式是否是诊断乳腺癌发生的免疫失调机制的基础。 AIM 1将纵向评估被诊断出患有早期乳腺癌的妇女，并评估其社会心理，皮质醇和免疫反应的轨迹，以及其外周血单核（PBMC）表观遗传学模式。在目标2和3中，这些关系将在细胞和分子水平上进行研究。 AIM 2将确定PBMC表观遗传模式是否与IFN伽马和/或穿孔蛋白的细胞水平的变化有关，这是癌症控制中的两个关键效应分子。 AIM 3将确定PBMC表观遗传模式是否与IFN Gamma和/或Perforin的启动子区域的染色质可及性的变化有关。最后，AIM 4将评估一个解释性模型，该模型提出了心理生物学变量之间的介导关系。潜在的生长曲线分析将用于识别和评估有关PBMC表观遗传模式的研究变量的轨迹。该项目将提供对免疫失调的机械理解，这是由于社会心理困扰而产生的，并有可能刺激开发新方法，以识别和管理面临心理困扰介导的免疫失调风险的人。 公共卫生相关性：承认会影响与癌症控制相关的免疫功能，但分子机制尚不清楚。一种未开发的可能性是，表观遗传修饰会导致免疫功能障碍，并研究对癌症患者免疫调节的表观遗传基础的研究将为心理社会治疗的影响提供新的洞察力，并将允许未来能够通过控制这种失调的手段发展。