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

基本信息

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
项目类别：
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&apos 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

项目摘要

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（适用提供）：环境不断变化，压力源很常见。对压力源的个人反应可能是适应性的或适应不良的。在细胞水平上，大部分响应通过调节基因组的结构和可及性来协调转录。人类基因组被包装并凝结成比染色体DNA长度小的六个数量级。凝结是通过将DNA包装在核心小体结构周围的DNA来完成的，这些核心小体结构被凝结成染色质。染色质冷凝的程度和性质决定了哪些基因的反映和转录哪些基因。我们已经证明了组蛋白表观遗传后翻译后修饰（表观遗传标记），以标记受心理压力不利影响的免疫反应基因。这种表观遗传标记决定了局部和全局染色质的可及性。该项目的重要目的是评估表观遗传标记和核结构蛋白，作为与诊断乳腺癌相关的心理压力引起的免疫调节指标。由于这些表观遗传标记和结构蛋白通过调节DNA结构域和单个基因调节元件之间的相互作用而导致基因表达，因此它们是进行此类评估的理想候选者。表观遗传标记和核结构蛋白将基因定位于活性转录部位（例如转录工厂）或基因失活或反射素（例如异染色质）的位点。因此，它们可能是理解细胞基础的关键，通过该基础，人们对心理压力源的反应会导致免疫失调，因为核染色质的压力相关的修饰可能与免疫细胞执行必要的免疫功能的能力直接相关。通过测量这些表观遗传标记和建筑蛋白来检测与压力相关的染色质组织，不仅可以提供对压力对染色质结构的影响的机械理解，而且还将为通过心理压力引起的免疫风险的个体检测个体的细胞仪手段提供基础。识别处于免疫学风险的人对妇女被诊断出患有乳腺癌。诸如乳腺癌之类的上皮性恶性肿瘤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害癌症的控制，尤其是在脆弱时期，例如手术后，立即调整疗法。由于心理压力，对处于免疫风险的个体的快速而适当的识别将使不仅在治疗后的直接治疗期间对这些人进行更激烈和仔细的监测，而且还可以融入其癌症轨迹，从而为早期的心理社会社会干预提供了机会。我们的小组和其他人已经证明了这种干预措施，以减少乳腺癌诊断的心理，身体和免疫学影响。