Cancer Control Research1R03CA168400-01
Flint, Melanie Sarah
IDENTIFYING UNDERLYING MECHANISMS OF INTRACELLULAR CHANGES IN RESPONSE TO CAREGIV
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. PUBLIC HEALTH RELEVANCE: This research will investigate the hypothesis that psychological stress on the caregiver negatively impacts T cell activation and migration by dys-regulation of key cytoskeletal and plasma membrane factors thus impacting overall health and wellbeing. Building on animal models, we will correlate defined T cell cytoskeletal proteins with psycho-behavioral responses such as caregiver anxiety, burden and depressive symptoms during the care trajectory and overall health. 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.