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，女性对乳腺癌的诊断有很大的心理社会困扰。来自心理神经免疫学的证据表明，心理社会困扰通过减少自然杀伤细胞活性（NKCA）和干扰素（IFN）γ的产生来损害免疫功能。NKCA和IFN γ均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，上皮肿瘤，如乳腺癌，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，诊断为乳腺癌的妇女经历心理社会困扰，这是伴随着皮质醇水平升高，NKCA减少，IFN γ的产生减少。本项目的目的是确定表观遗传模式是否是乳腺癌诊断中发生的免疫失调机制的基础。目标1将纵向评估诊断为早期乳腺癌的女性，并评估其心理社会，皮质醇和免疫反应的轨迹与外周血单核细胞（PBMC）表观遗传模式。在目标2和3中，将在细胞和分子水平上研究这些关系。目的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）的细胞水平变化相关。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的染色质可及性变化相关。最后，目标4将评估一个解释性模型，假定心理生物学变量之间的中介关系。将使用潜在生长曲线分析来识别和评价研究变量在PBMC表观遗传模式方面的轨迹。该项目将提供一个机制的理解免疫失调，随之而来的心理困扰，并有可能刺激新的方法来识别和管理个人的心理困扰介导的免疫失调的风险发展。

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.