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

基本信息

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
项目类别：
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

项目摘要

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)，最常见的 PMBT（IV 级星形细胞瘤）患者的五年生存率低于 25 %。脑肿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，这需要家庭成员在家中积极参与患者的护理。目前美国大约有 6570 万名护理人员（占人口的 29%）。如果他们的健康得不到保护，护理人员身体健康状况不佳会给医疗保健系统带来额外的压力，并且家庭护理可能会受到影响。事实上，提供护理对护理人员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）已有充分记录。研究表明，承受高压力的护理人员对病毒感染、过敏和自身免疫反应以及过早冠心病的易感性增加。尽管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，心理压力会影响免疫的多个方面，包括淋巴细胞活化和迁移。成功的免疫反应取决于有效的抗原启动、强大的 T 细胞激活以及效应器在目标解剖部位的迁移。迄今为止，护理人员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、尚未被充分理解的过程。然而，众所周知，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局部相互作用的协调决定了 T 细胞反应的性质和程度。对于控制应激和 T 细胞之间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分析表明，压力可以引发几种重要的肌动蛋白调节蛋白的显着变化。用于啮齿类动物 T 细胞骨架重排和细胞迁移。当前的提案旨在将这种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，以评估脑肿瘤患者家庭护理人员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资助中评估的一段时间内的心理行为反应相关联，从而对整体健康产生负面影响。为了检验护理人员压力通过调节关键细胞骨架和质膜因子对 T 细胞激活和迁移产生负面影响的假设，我们将检查 PMBT 患者护理人员群体中控制 T 细胞激活/抑制和迁移的 T 细胞蛋白经历急性发作和慢性的应激反应。将在诊断时以及 4、8 和 12 个月时从 15 名护理人员处采集血样。将通过定量质谱分析 T 细胞，以确定导致 T 细胞功能障碍的肌动蛋白依赖性信号通路，并且还将评估 T 细胞功能。该提案将是第一个从分子角度分析心理压力对人类循环 T 淋巴细胞综合蛋白质组影响的提案。确定的 T 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联；护理过程中护理人员的焦虑、负担、抑郁症状和整体身体健康状况。该项目的成功完成将使人们更好地了解负责 T 细胞调节的新型应激诱导机制。获得的数据对于识别有负面结果风险的护理人员以改善护理人员的整体健康至关重要。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

应激激素通过诱导 DNA 损伤降低紫杉醇治疗三阴性乳腺癌的疗效。

DOI：
发表时间：
2015-04-28
期刊：
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