Immune dysregulation by psychosocial distress

描述(由申请人提供)：乳腺癌的诊断以及乳腺癌治疗的负担使妇女面临心理社会痛苦的风险。心理社会困扰会损害免疫系统，影响自然杀伤细胞和细胞因子的产生。这对乳腺癌患者特别重要，因为乳腺癌可以对自然杀伤细胞和细胞因子产生反应。免疫系统的这些组成部分通过保护肿瘤免受肿瘤起始、原发肿瘤生长和肿瘤转移的影响，有助于癌症控制。在过去的十年中，被诊断为导管原位癌(DCIS)的乳腺癌的妇女人数显著增加。DCIS患者数量的增加是由于高分辨率筛查乳房X光检查的广泛使用。DCIS是一个重大的临床管理问题，被诊断为DCIS的女性面临着艰难的治疗选择，这些选择不仅必须与癌症复发的风险权衡，还必须考虑她们的个人价值观。我们的初步数据显示，患有DCIS的女性经历了心理社会痛苦，其特征是情绪障碍、焦虑和感知到的压力升高。伴随着这种心理社会困扰的是免疫失调，其特征是自然杀伤细胞功能降低和细胞因子干扰素γ的产生减少。这种对免疫系统的影响可能会对乳腺癌患者的整体健康和生活质量产生相当大的影响。然而，令人惊讶的是，人们对观察到的免疫失调的分子基础知之甚少。这个项目的总体目的是在分子水平上确定这种免疫失调的基础。这种鉴定将通过确定心理社会痛苦后的外周血单核细胞表观遗传修饰是否介导免疫失调来完成。该项目的具体目标是：1)在被诊断为DCIS的女性中，确定与心理社会困境介导的免疫失调相关的外周血单核细胞表观遗传模式。2)评估表观遗传修饰是否与DCIS女性特定的免疫应答基因失调有关。这一为期两年的发展/试点(R21)项目将在两个数据收集时期对DCIS妇女进行评估，一个时期是在乳腺癌诊断之后，一个是在癌症治疗完成后两个月。结果将与一组匹配的女性进行对比。该项目的设计将提供外周血单核细胞亚群的鉴定，并进行明显的表观遗传模式修改。一旦确定，这些亚群将通过染色质免疫沉淀和聚合酶链式反应进行评估，以确定观察到的表观遗传效应是否与这些女性体内特定免疫反应基因的调控区域有关。以前还没有完成过这样的分析，这项研究将首次调查心理社会困境对免疫系统的表观遗传学影响。识别这种免疫失调的表观遗传学基础将为心理社会痛苦的影响提供新的见解，并将允许未来开发管理这种失调的方法。这样的管理不仅将减少免疫失调的长期不利影响，而且还将改善这些患者的整体健康和生活质量。

DESCRIPTION (provided by applicant): Diagnosis of breast cancer as well as the burden of breast cancer treatment put women at risk for psychosocial distress. Psychosocial distress impairs the immune system, impacting both natural killer cells and the production of cytokines. This is of particular importance to breast cancer patients because breast cancer can be responsive to natural killer cells and cytokines. These components of the immune system contribute to cancer control by protection from tumor initiation, primary tumor growth, and tumor metastasis. In the past decade, the number of women diagnosed with the form of breast cancer known as ductal carcinoma in situ (DCIS) has markedly increased. This increase in the number of DCIS patients is due to the widespread use of high- resolution screening mammography. DCIS is a significant clinical management problem and women diagnosed with DCIS face difficult treatment choices that must be weighed against not only the risk of cancer recurrence but also their personal values. Our preliminary data show that women with DCIS experience psychosocial distress that is characterized by elevated mood disturbance, anxiety, and perceived stress. Accompanying this psychosocial distress is immune dysregulation characterized by reduced natural killer cell function and reduced production of the cytokine interferon y. Such effects upon the immune system may have considerable impact upon the overall health and quality of life of breast cancer patients. However, surprisingly little is known about the molecular basis for the observed immune dysregulation. It is the overall purpose of this project to identify, at the molecular level, the basis for this immune dysregulation. This identification will be accomplished by determining whether peripheral blood mononuclear cell epigenetic modifications, subsequent to psychosocial-distress, mediate the immune-dysregulation. The specific aims of the project are to: 1) Identify peripheral blood mononuclear cell epigenetic patterns associated with psychosocial-distress mediated immune-dysregulation in women who are diagnosed with DCIS. 2) Evaluate whether epigenetic modifications are associated with specific dysregulated immune response genes in women with DCIS. This two-year developmental/pilot (R21) project will evaluate women with DCIS at 2 data collection time periods, one following breast cancer diagnosis and one 2 months after completion of cancer treatment. Results will be contrasted with a comparison group of matched women. The design of this project will provide for an identification of the peripheral blood mononuclear cell subsets, with demonstrable epigenetic pattern modification. Once identified, these subsets will be evaluated by chromatin immunoprecipitation and polymerase chain reaction to determine whether the observed epigenetic effects are associated with regulatory regions of specific immune response genes dysregulated in these women. No such analysis has been accomplished previously and this study will provide the first investigation of the epigenetic effects of psychosocial distress upon the immune system. Identification of an epigenetic basis for this immune-dysregulation 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. Such management will not only reduce the long-term adverse effects of immune-dysregulation but will also improve the overall health and quality of life of these patients.