Chromatin organization as a predictor of stress induced immune dysregulation

染色质组织作为应激引起的免疫失调的预测因子

• 批准号: 9245665
• 负责人: Linda Janusek
• 金额: $ 52.33万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9245665
• 关键词: Active Sites; Address; Adjuvant Therapy; Affect; Aftercare; Age; Architecture; Behavioral Symptoms; Biological; Breast Cancer Patient; Breast Cancer survivorship; Cancer Control; Cancer Patient; Cancer Survivorship; Cell Nucleus; Cells; Characteristics; Chromatin; Chromatin Structure; Chromosome Mapping; DNA; DNA Packaging; Data; Detection; Diagnosis; Enrollment; Environment; Epigenetic Process; Epithelial; Evaluation; Exhibits; Exposure to; Future; Gene Expression; Gene Silencing; Genes; Genetic Transcription; Genome; Global Change; Heart; Heterochromatin; Histones; Human Genome; Hydrocortisone; Image; Immune; Immune Response Genes; Immune System Diseases; Immune System and Related Disorders; Immune response; Immune system; Immunologic Surveillance; Immunologics; Impairment; Individual; Individual Differences; Intervention; Length; Life; Malignant Neoplasms; Measurement; Mediating; Mediation; Modeling; Modification; Molecular; Monitor; Nature; Neurosecretory Systems; Nuclear; Nucleosome Core Particle; Operative Surgical Procedures; Pathway interactions; Pattern; Perception; Peripheral Blood Mononuclear Cell; Phenotype; Physical condensation; Physiological; Post-Translational Protein Processing; Proteins; Psychological Stress; Regulator Genes; Regulatory Element; Reporting; Risk; Site; Stress; Structure; Testing; Woman; Women' s Group; antitumor effect; behavioral response; biological adaptation to stress; breast cancer diagnosis; cancer care; cancer diagnosis; experience; high risk; immune function; improved; indexing; malignant breast neoplasm; molecular marker; prospective; psychologic; psychological stressor; psychosocial; public health relevance; response; stressor; survivorship; treatment duration

 DESCRIPTION (provided by applicant): Environments are ever-changing and stressors commonplace. Individual response to a stressor can be adaptive or maladaptive. At the cellular level, much of the response is coordinated transcriptionally by modulating the structure and accessibility of the genome. The human genome is packaged and condensed into nuclei six orders of magnitude smaller than the length of chromosomal DNA. Condensation is accomplished by packaging DNA around core nucleosome structures that are condensed into chromatin. The degree and nature of chromatin condensation determines which genes are repressed and which genes are transcribed. We have demonstrated histone epigenetic post-translational modifications (epigenetic marks) to mark immune response genes that are adversely affected by psychological stress. Such epigenetic marks determine local and global chromatin accessibility. It is the significant purpose of this project to evaluate both epigenetic marks and nuclear architectural proteins as indices of the immune dysregulation resultant from the psychological stress associated with a diagnosis of breast cancer. Because these epigenetic marks and architectural proteins contribute to gene expression by regulating interactions among DNA domains and among individual gene regulatory elements, they are ideal candidates for such an evaluation. Epigenetic marks and nuclear architectural proteins localize genes to sites of active transcription (e.g. transcription factories) or to sites of gene inactivation or repressin (e.g. heterochromatin). As such they may hold the key to understanding the cellular basis by which one's response to a psychological stressor leads to immune dysregulation, in that stress related modification of nuclear chromatin may directly relate to the capacity of immune cells to carry out necessary immune functions. Detection of stress related chromatin organization by measurement of these epigenetic marks and architectural proteins will provide not only for a mechanistic understanding of the effects of stress upon chromatin structure but will also provide the basis for a cytometric means by which to detect individuals at immunological risk due to psychological stress. Identification of individuals at immunologic risk is especially important for women diagnosed with breast cancer. Epithelial malignancies, like breast cancer, are responsive to immune surveillance and to the anti- tumor effects of the immune system. As such, psychological stress that impacts these forms of immune surveillance would jeopardize cancer control, especially during vulnerable periods, e.g. after surgery and immediately post adjuvant therapy. Quick and appropriate identification of individuals at immunologic risk, due to psychological stress, would allow for more intense and careful monitoring of those individuals not just during the immediate post-treatment period but well into their cancer trajectory, providing the opportunity for early psycho-social intervention. Such interventions have been demonstrated by our group and others to reduce the psychological, physiological and immunological impact of a diagnosis of breast cancer.

 描述（由申请人提供）：环境是不断变化的，压力源司空见惯。个体对压力源的反应可以是适应性的，也可以是适应不良的。在细胞水平上，许多反应通过调节基因组的结构和可及性来转录协调。人类基因组被包装并浓缩成比染色体DNA长度小六个数量级的细胞核。浓缩是通过将DNA包装在浓缩成染色质的核心核小体结构周围来完成的。染色质凝聚的程度和性质决定了哪些基因被抑制，哪些基因被转录。我们已经证明了组蛋白表观遗传翻译后修饰（表观遗传标记），以标记免疫反应基因，心理压力的不利影响。这种表观遗传标记决定了局部和全局染色质的可及性。本项目的重要目的是评估表观遗传标记和核结构蛋白作为与乳腺癌诊断相关的心理压力引起的免疫失调的指标。由于这些表观遗传标记和结构蛋白通过调节DNA结构域之间和单个基因调控元件之间的相互作用而促进基因表达，因此它们是这种评估的理想候选者。表观遗传标记和核结构蛋白将基因定位于活跃转录的位点（例如转录工厂）或基因失活或阻遏蛋白的位点（例如异染色质）。因此，它们可能是理解一个人对心理应激源的反应导致免疫失调的细胞基础的关键，因为核染色质的应激相关修饰可能直接与免疫细胞执行必要的免疫功能的能力有关。通过测量这些表观遗传标记和结构蛋白来检测与应激相关的染色质组织，不仅可以从机理上理解应激对染色质结构的影响，而且还可以为细胞计数手段提供基础，通过该手段来检测由于心理应激而处于免疫风险中的个体。识别具有免疫风险的个体对于以下方面尤其重要： 被诊断为乳腺癌上皮恶性肿瘤，如乳腺癌，对免疫监视和免疫系统的抗肿瘤作用有反应。因此，影响这些形式的免疫监视的心理压力会危及癌症控制，特别是在脆弱时期，例如手术后和辅助治疗后立即。快速和适当地识别由于心理压力而处于免疫风险中的个体，将允许对这些个体进行更密集和仔细的监测，不仅在治疗后阶段，而且在其癌症轨迹中，为早期心理社会干预提供机会。我们小组和其他人已经证明这种干预措施可以减少乳腺癌诊断的心理，生理和免疫影响。