Identifying underlying mechanisms of intracellular changes in response to caregiv

描述(申请人提供)：在美国，每年有超过51,000人被诊断出患有原发恶性脑瘤(PMBT)，而最常见的PMBT患者的五年生存率不到25%，这是一种IV级星形细胞瘤。脑瘤的肿瘤和神经后遗症会导致患者的身体和认知状态发生多种变化，这需要家人在家中非常积极地参与患者的护理。目前美国约有6570万照顾者(占总人口的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会给医疗体系带来额外的压力，家庭护理可能会受到影响。事实上，提供护理对照顾者的心理和身体健康(例如，高度抑郁症状、负担、焦虑和报告总体健康状况不佳)的影响已经有了很好的记录。报告压力大的照顾者被证明对病毒感染、过敏和自身免疫反应以及过早的冠状动脉疾病的易感性增加。尽管数据已经确立了负面的心理和整体健康反应，但提供护理的压力导致整体健康状况不佳的生物学途径一直研究得很少。据报道，心理应激会影响免疫的几个方面，包括淋巴细胞的激活和迁移。成功的免疫反应依赖于有效的抗原启动、强大的T细胞激活和效应器在目标解剖位置的迁移。到目前为止，护理者文献中的大多数研究都是在体内进行的，缺乏体外数据。T细胞的迁移是一个复杂的、尚未被很好理解的过程；然而，已知的是一个具有功能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细胞之间交流的细胞内和细胞间机制，人们知之甚少。然而，我们先前广泛的蛋白质组学分析显示，压力可以触发几个重要的肌动蛋白调节蛋白的显著变化。 用于啮齿动物T细胞骨架重排和细胞迁移。目前的建议旨在将这一分子和机制维度添加到正在进行的纵向描述性研究(R01 CA117811；Sherwood Pi)中，评估脑肿瘤患者家庭照顾者的生物行为交互作用。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体)中细胞骨架蛋白的解除管制如何与父母赠款中评估的随着时间的推移而做出的心理行为反应相关，从而对整体健康产生负面影响。为了验证照顾者应激通过调节关键的细胞骨架和质膜因素而对T细胞的激活和迁移产生负面影响的假设，我们将研究控制T细胞激活/抑制和迁移的T细胞蛋白，在PMBT患者经历急性和慢性应激反应的照顾者群体中。在确诊时、4个月、8个月和12个月时，将从15名照顾者身上采集血液样本。将用定量质谱仪分析T细胞，以确定导致T细胞功能障碍的肌动蛋白依赖的信号通路，并对T细胞功能进行评估。这项提议将是第一个从分子角度分析心理应激对人类循环T淋巴细胞综合蛋白质组的影响。确定的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：照顾者在护理轨迹中的焦虑、负担、抑郁症状和整体身体健康。这个项目的成功完成将提供对T细胞调节的新的应激诱导机制的更好的理解。所获得的数据将是确定照顾者面临负面后果风险以改善整体照顾者健康的关键。

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.