Identifying underlying mechanisms of intracellular changes in response to caregiv

描述（由申请人提供）：在美国，每年有超过51,000人被诊断为原发性恶性脑肿瘤（PMBT），最常见的PMBT （IV级星形细胞瘤）患者的5年生存率低于25%。脑肿瘤的肿瘤和神经系统后遗症会引起患者身体和认知状态的多种变化，这就需要家庭成员在家中对患者进行非常积极的照顾。目前在美国大约有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损害。事实上，提供照料对照料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）已得到充分记录。报告压力大的护理人员更容易受到病毒感染、过敏和自身免疫反应以及过早患上冠状动脉疾病。虽然数据已经确定了消极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学途径的研究还远远不够。据报道，心理应激会影响免疫的几个方面，包括淋巴细胞活化和迁移。成功的免疫应答依赖于有效的抗原启动、强大的T细胞激活和效应物在目标解剖部位的迁移。迄今为止，护理文献中的大多数研究都是在体内进行的；缺乏体外实验数据。t细胞迁移是一个复杂的，尚未被充分理解的过程；然而，众所周知，功能性的细胞骨架和肌动蛋白聚合是必不可少的。此外，受体与细胞的肌动蛋白-细胞骨架之间的局部相互作用的协调决定了t细胞反应的性质和强度。对于控制应激和T细胞之间的通讯的细胞内和细胞间机制知之甚少。然而，我们之前广泛的蛋白质组学分析显示，压力可以触发几个重要的肌动蛋白调节蛋白的显著变化

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.