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名患有原发性恶性脑肿瘤（PMBT）和最常见的PMBT患者（星形胶质细胞瘤IV级）的五年生存率，小于25％。脑肿瘤的肿瘤学和神经后遗症引起了患者的身体和认知状况的多种变化，这要求家人在家中非常参与患者的护理。目前，美国约有6570万看护人（占29％的人口）。如果没有保留健康，则照顾者的身体健康状况不佳将对医疗保健系统施加额外的压力，而家庭的家庭护理可能会受到损害。确实，提供护理对看护人心理和身体健康的影响（例如，高水平的抑郁症状，负担，焦虑和整体健康状况不佳的报告）已得到充分证明。报告的高水平压力的护理人员已显示出对病毒感染，过敏和自身免疫性反应以及过早冠状动脉疾病的敏感性增加。尽管数据已经建立了负面的心理和整体健康反应，但提供护理压力导致整体健康状况不佳的生物学途径已被大量研究。据报道，心理压力会影响免疫的几个方面，包括淋巴细胞激活和迁移。成功的免疫反应取决于有效的抗原启动，稳健的T细胞激活以及目标解剖部位的效应子的迁移。迄今为止，在体内进行了大多数护理人员文献研究。缺乏体外数据。 T细胞迁移是一个复杂的，尚不清楚的过程。然而，众所周知，功能性细胞骨架和肌动蛋白聚合至关重要。此外，受体与细胞肌动蛋白细胞骨架之间局部相互作用的协调决定了T细胞反应的性质和幅度。关于控制压力与T细胞之间通信的细胞内机制和细胞间机制知之甚少。但是，我们以前的广泛蛋白质组学分析表明，压力可以引发几种调节蛋白质重要的肌动蛋白的重大变化 用于T细胞细胞骨架重排和啮齿动物的细胞迁移。当前的建议旨在将此分子和机械维度添加到正在进行的纵向描述性研究（R01 CA117811; Sherwood PI）中，评估了患有脑肿瘤患者的家庭护理者的生物行为相互作用。这项拟议的研究的最终目标是确定T细胞中细胞骨架蛋白（适应性免疫系统的主要介体）中的细胞骨架蛋白的放松如何与父母赠款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。为了测试护理人应力通过调节关键细胞骨架和质膜因子的调节对T细胞激活和迁移的假设，我们将检查T细胞蛋白，这些T细胞蛋白在PMBT伴有急性压力反应的人群中控制T细胞激活/抑制和迁移的T细胞激活/抑制和迁移。在诊断时，在4、8和12个月时，将从15名护理人员中采集血液样本。 T细胞将通过定量质谱法分析，以识别依赖性肌动蛋白依赖性信号通路，这些信号通路有助于T细胞功能障碍，也将评估T细胞功能。该提案将是分子分子对人类循环T淋巴细胞综合蛋白质组进行分子压力影响的第一个此类建议。定义的T细胞细胞骨架蛋白将以靶向方式与以下心理行为反应相关。护理人员焦虑，负担，抑郁症状和护理轨迹的整体身体健康。该项目的成功完成将更好地理解针对T细胞调节的新型应力诱导的机制。获得的数据对于识别有负面结果的护理人员以改善整体护理人员的健康至关重要。

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.