Immune dysregulation by psychosocial distress

心理社会困扰导致的免疫失调

• 批准号: 8434283
• 负责人: Linda Janusek
• 金额: $ 51.04万
• 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/8434283
• 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.

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。毫不奇怪，女性在诊断出乳腺癌后会出现严重的社会心理困扰。心理神经免疫学证据表明，社会心理困扰会降低自然杀伤细胞活性 (NKCA) 和干扰素 (IFN) 的产生，从而损害免疫功能。 NKCA 和 IFN γ 都有助于防止肿瘤发生、原发性肿瘤生长和肿瘤转移。值得注意的是，上皮性肿瘤（如乳腺肿瘤）对 NK 细胞和 IFN γ 有反应。因此，这些形式的免疫防御的减少与乳腺癌有关。我们发现，被诊断患有乳腺癌的女性会经历社会心理困扰，伴随着皮质醇水平升高、NKCA 降低和 IFN γ 产生减少。该项目的目的是确定表观遗传模式是否是乳腺癌诊断时发生的免疫失调机制的基础。目标 1 将纵向评估被诊断为早期乳腺癌的女性，并评估其心理社会、皮质醇和免疫反应相对于外周血单核 (PBMC) 表观遗传模式的轨迹。在目标 2 和 3 中，将在细胞和分子水平上研究这些关系。目标 2 将确定 PBMC 表观遗传模式是否与 IFN γ 和/或穿孔素（癌症控制中的两种关键效应分子）细胞水平的变化相关。目标 3 将确定 PBMC 表观遗传模式是否与 IFN γ 和/或穿孔素启动子区域染色质可及性的变化相关。最后，目标 4 将评估一个解释模型，该模型假定心理生物学变量之间的中介关系。潜在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。该项目将提供对社会心理困扰导致的免疫失调的机制理解，并有可能刺激开发新方法来识别和管理面临心理社会困扰介导的免疫失调风险的个体。