Immune dysregulation by psychosocial distress

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，女性对乳腺癌诊断的反应是严重的心理社会困扰。来自精神神经免疫学的证据表明，社会心理困扰通过降低自然杀伤细胞活性（NKCA）和干扰素(IFN) γ的产生来损害免疫功能。NKCA和IFN γ对肿瘤起始、原发肿瘤生长和肿瘤转移都有保护作用。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心理社会困扰，并伴有皮质醇水平升高、NKCA下降和IFN γ产生减少。该项目的目的是确定表观遗传模式是否为乳腺癌诊断时发生的免疫失调机制奠定了基础。目的1将对诊断为早期乳腺癌的女性进行纵向评估，并评估她们的社会心理、皮质醇和免疫反应的轨迹，以及她们的外周血单核（PBMC）表观遗传模式。在目标2和目标3中，这些关系将在细胞和分子水平上进行研究。目的2将确定PBMC表观遗传模式是否与细胞中IFN γ和/或穿孔素水平的变化有关，这是癌症控制中的两个关键效应分子。目的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有关。最后，目的4将评估一个解释模型，该模型假设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关于PBMC表观遗传模式的研究变量的轨迹。该项目将提供免疫失调的机制理解，由此导致的社会心理困扰，并有可能促进新方法的发展，以识别和管理有社会心理困扰介导的免疫失调风险的个体。

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.