Identifying underlying mechanisms of intracellular changes in response to caregiv

识别响应护理的细胞内变化的潜在机制

• 批准号: 8539752
• 负责人: CAROLA ANKE NEUMANN
• 金额: $ 7.18万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-04 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8539752
• 关键词: Actins; Acute; Adrenergic beta-Antagonists; Affect; Animal Model; Antigens; Anxiety; Autoimmune Responses; B-Lymphocytes; Behavioral; Binding; Biological; Blood specimen; Brain Neoplasms; Caregiver Burden; Caregivers; Caring; Cell membrane; Cell physiology; Cells; Chronic; Chronic stress; Cognitive; Communication; Complex; Coronary heart disease; Cytoskeletal Proteins; Cytoskeleton; DNA Sequence Rearrangement; Data; Diagnosis; Dimensions; Disease; Exposure to; Family; Family Caregiver; Family member; Figs - dietary; Functional disorder; Glioblastoma; Goals; Health; Healthcare Systems; Home environment; Hormone Receptor; Human; Immigration; Immune response; Immune system; Immunity; Immunotherapy; In Vitro; Individual; Literature; Lymphocyte Activation; Lymphoid; Malignant Neoplasms; Malignant neoplasm of brain; Mass Spectrum Analysis; Mediator of activation protein; Mental Health; Molecular; Monitor; Natural Immunity; Natural Killer Cells; Nature; Neurologic; Organ; Outcome; Pathway interactions; Patient Care; Patients; Persons; Phenotype; Population; Predisposition; Process; Production; Proteins; Proteome; Proteomics; Psychological Stress; Regulation; Reporting; Research; Research Personnel; Risk; Rodent; Signal Pathway; Site; Spleen; Stress; T cell regulation; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Time; United States; Virus Diseases; Work; adaptive immunity; allergic response; base; biobehavior; biological adaptation to stress; cell motility; cytokine; depressive symptoms; design; disorder risk; genetic regulatory protein; improved; in vivo; lymph nodes; migration; novel; novel therapeutic intervention; parent grant; physical conditioning; polymerization; premature; protein function; psychologic; receptor; response

DESCRIPTION (provided by applicant): Each year in the United States more than 51,000 individuals are diagnosed with a primary malignant brain tumor (PMBT) and the five year survival of patients with the most common PMBT, an astrocytoma grade IV, is less than 25%. The oncological and neurological sequelae of a brain tumor induce multiple changes in the patient's physical and cognitive status, which require family members to be very involved in care of the patient at home. There are approximately 65.7 million caregivers (29% of the population) currently in the United States. If their health is not preserved, poor physical health of caregiver will place additional stress on the healthcare system and family care in the home may be compromised. Indeed, the impact of providing care on caregivers' psychological and physical health (e.g., high levels of depressive symptoms, burden, anxiety and reports of poor overall health), has been well documented. Caregivers who report high levels of stress have been shown to have increased susceptibility to viral infections, allergic and autoimmune responses and premature coronary disease. Although data have established negative psychological and overall health responses, the biological pathways through which the stress of providing care leads to poor overall health has been vastly understudied. Psychological stress has been reported to affect several aspects of immunity including lymphocyte activation and migration. A successful immune response depends on effective antigen priming, robust T cell activation and migration of effectors at target anatomical sites. Most research in the caregiver literature has thus far been performed in vivo; in vitro data are lacking. T-cell migration is a complex, not yet well understood process; however it is known that a functional cytoskeleton and actin polymerization is essential. Moreover, the coordination of the local interactions between receptors with the cell's actin-cytoskeleton determines the nature and magnitude of T-cell responses. Little is known about the intra- and inter-cellular mechanisms which govern communication between stress and T cells. However, our previous extensive proteomic profiling revealed that stress can trigger significant changes in several actin regulating proteins important for T cell cytoskeletal rearrangement and cell migration in rodents. The current proposal is designed to add this molecular and mechanistic dimension to an ongoing longitudinal descriptive study (R01 CA117811; Sherwood PI) evaluating bio behavioral interaction in family caregivers of persons with a brain tumor. The ultimate goal of this proposed research is to determine how deregulation of cytoskeletal proteins in T cells (the major mediators of the adaptive immune system) correlate with psycho behavioral responses over time assessed in the parent grant thus negatively impacting overall health. To test the hypothesis that caregiver stress negatively impacts T cell activation and migration through regulation of key cytoskeletal and plasma membrane factors, we will examine the T cell proteins which govern T cell activation/suppression and migration in a population of caregivers of persons with a PMBT undergoing a stress response with an acute onset and chronic nature. Blood samples will be taken from 15 caregivers at time of diagnosis, and at 4, 8 and 12 months. T cells will be analyzed by quantitative mass spectrometry to identify actin dependent signaling pathways which contribute to T cell dysfunction and T cell function will also be assessed. This proposal will be the first of its kind to molecularly analyze psychological stress effects on the comprehensive proteome of circulating T lymphocytes in humans. Defined T cell cytoskeletal proteins will be correlated in a targeted fashion with the following psycho-behavioral responses; caregiver anxiety, burden, depressive symptoms and overall physical health during the care trajectory. Successful completion of this project will provide a better understanding of novel stress-induced mechanisms responsible in T cell regulation. The data obtained will be critical in identifying caregivers at risk for negative outcomes to improve overall caregiver health.

描述（由申请人提供）：在美国，每年有超过51，000人被诊断患有原发性恶性脑肿瘤（PMBT），并且患有最常见的PMBT（星形细胞瘤IV级）的患者的五年生存率低于25%。脑肿瘤的肿瘤学和神经学后遗症引起患者身体和认知状态的多种变化，这需要家庭成员在家中非常参与患者的护理。目前，美国约有6570万护理人员（占人口的29%）。如果他们的健康得不到保护，照顾者的身体健康状况不佳将给医疗保健系统带来额外的压力，家庭护理可能会受到影响。事实上，提供护理对照顾者心理和身体健康的影响（例如，严重的抑郁症状、负担、焦虑和总体健康状况不佳的报告）。报告高水平压力的护理人员已被证明对病毒感染，过敏和自身免疫反应以及过早的冠心病的易感性增加。虽然数据已经确定了负面的心理和整体健康反应，但对提供护理的压力导致整体健康状况不佳的生物途径的研究还远远不够。心理压力已被报道影响免疫的几个方面，包括淋巴细胞活化和迁移。成功的免疫应答取决于有效的抗原引发、稳健的T细胞活化和效应子在靶解剖部位的迁移。迄今为止，护理文献中的大多数研究都是在体内进行的，缺乏体外数据。T细胞迁移是一个复杂的，尚未完全理解的过程;然而，已知功能性细胞骨架和肌动蛋白聚合是必不可少的。此外，受体与细胞肌动蛋白细胞骨架之间的局部相互作用的协调决定了T细胞反应的性质和大小。关于控制应激和T细胞之间的通信的细胞内和细胞间机制知之甚少。然而，我们先前广泛的蛋白质组学分析显示，压力可以引发几种重要的肌动蛋白调节蛋白的显着变化， T细胞骨架重排和细胞迁移。当前提案旨在将该分子和机制维度添加到正在进行的纵向描述性研究（R 01 CA 117811;舍伍德PI）中，该研究评价脑肿瘤患者家庭护理者的生物行为相互作用。这项拟议研究的最终目标是确定T细胞（适应性免疫系统的主要介质）中细胞骨架蛋白的失调如何与父母补助金中评估的心理行为反应相关，从而对整体健康产生负面影响。为了检验这一假设，照顾者的压力产生负面影响T细胞的活化和迁移，通过调节关键的细胞骨架和质膜因子，我们将检查T细胞蛋白，管理T细胞的活化/抑制和迁移的人与PMBT的照顾者的人口经历了急性发作和慢性性质的应激反应。将在诊断时以及4、8和12个月时从15名护理人员中采集血液样本。将通过定量质谱法分析T细胞以鉴定促成T细胞功能障碍的肌动蛋白依赖性信号传导途径，还将评估T细胞功能。这一提议将是第一个从分子水平上分析心理应激对人类循环T淋巴细胞综合蛋白质组影响的研究。定义的T细胞细胞骨架蛋白将以有针对性的方式与以下心理行为反应相关;护理轨迹期间的护理者焦虑，负担，抑郁症状和整体身体健康。该项目的成功完成将使人们更好地理解T细胞调节中新的应激诱导机制。所获得的数据将是至关重要的，以确定护理人员在风险的负面结果，以改善整体护理人员的健康。

项目成果

Stress hormones reduce the efficacy of paclitaxel in triple negative breast cancer through induction of DNA damage.

• DOI: 10.1038/bjc.2015.133
• 发表时间: 2015-04-28
• 期刊: BRITISH JOURNAL OF CANCER
• 影响因子: 8.8
• 作者: Reeder, A.;Attar, M.;Nazario, L.;Bathula, C.;Zhang, A.;Hochbaum, D.;Roy, E.;Cooper, K. L.;Oesterreich, S.;Davidson, N. E.;Neumann, C. A.;Flint, M. S.
• 通讯作者: Flint, M. S.