Immune dysregulation by psychosocial distress

心理社会困扰导致的免疫失调

基本信息

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
项目类别：
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

项目摘要

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。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困扰介导的免疫失调风险的个体。公共健康相关性：人们承认社会心理困扰会影响与癌症控制相关的免疫功能，但其分子机制尚不清楚。一种尚未探索的可能性是，表观遗传修饰会导致免疫功能障碍，对癌症患者免疫失调的表观遗传基础的研究将为了解社会心理困扰的影响提供新的见解，并为未来开发管理这一问题的方法奠定基础。失调。