Jason R. Yee - US grants

[unreadable] DESCRIPTION (provided by applicant): Breast cancer is the leading cause of cancer in women and only 10% of cases thought to be caused by inherited germline mutations, suggesting a strong role for the interaction between environmental stressors and genetic predisposition. The aim of this proposal is to characterize how breast carcinogenesis is modulated by psychological traits and social circumstances that cause stress over the life-span. In rats, fearful temperament, lack of reciprocal social support, and social isolation confer an increased risk for spontaneous tumorigenesis and early mortality. Greater than 40% of tumors are malignant ductal carcinomas or pre-malignant ductal carcinoma in situ (DCIS). It is hypothesized that the endogenous regulation of glucocorticoid release in response to stress partially mediates this effect by suppressing apoptosis in neoplastic cells. To determine which phases of the carcinogenic process are amenable to psychosocial modulation, female rats will be administered 7,12-dimethylbenz(a)anthracene (DMBA), a well- characterized chemical carcinogen known to initiate mammary tumorigenesis. A subset of rats will be sacrificed 8 days following DMBA administration, the start of a 2-week critical period for tumor promotion, to measure rates of apoptosis and proliferation in the mammary epithelium. Another subset will be maintained until 50% of the population has developed at least one reliably palpable mammary tumor. Standardized tumor initiation will reveal whether subsequent phases of the carcinogenic process can be modulated by psychological traits and social circumstances that predispose stress over the life-span. A second related study will examine the role of life-long psychosocial factors in mammary development. The degree to which developing mammary glands are exposed to pre-cyclic ovarian hormone dynamics is hypothesized to be a strong risk factor for mammary carcinogenesis. We will test whether psychological traits and social circumstances that cause life-long stress predispose a carcinogenic hormonal environment by (1) tracking the onset of estrous cycles and (2) characterizing mammary development from puberty to young adulthood. Together, these studies will offer new insights into the psychological and social regulation of breast cancer by testing whether psychosocial factors affect tumor development and growth, and do so through the endogenous regulation of hormones. As such, these studies will also allow an estimation of the proportion of the racial disparity in breast cancer that can be explained by social inequalities. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Social relationships have a significant effect on overall health, and the bereavement and grief associated with losing a close relationship is associated with increased rates of morbidity and mortality. The general j goal of this application is to begin deconstructing the mechanisms through which social relationships are beneficial to mental and physical health, especially in aging. The hypothesis to be examined suggests that oxytocin (OT) plays a central role in buffering against emotional and autonomic reactivity, including stress and anxiety which may have broad consequences for health in old age. To dissect the physiological j mechanisms that underie the connection between stress and sociality, we will use the prairie vole (Microtus j ochrogaster), an animal similar to humans (but unique among rodents) in its tendency to form selective, long-lasting social bonds. Prairie voles also have a human-like autonomic nervous system and produce high levels of OT, making them an ideal model for translational studies on the mechanisms underlying the connection between social relationships and health. The proposed integrative experiments will examine behavioral, neuroendocrine and autonomic changes: following social separation and isolation, as a function of the presence or absence of OT. Research has shown that OT promotes social affiliation and buffers against stressors. However, recent work has also shown that OT is heightened after a long period of separation from a familiar social partner. The experiments proposed herein will closely examine the function of this separation-induced rise in OT by administering exogenous OT, or by blocking the actions of endogenous OT with a selective antagonist. Comparisons between central and peripheral administrations will demonstrate where OT is acting to produce changes in the emotional and physiological reactivity to stressors. Clarifying the mechanisms through which- social separation and isolation lead to detrimental changes will ultimately result in more targeted therapeutic approaches that hold promise for both prevention and treatment of age-related disease. 1: The loss of close social relationships, especially in old age, is potentially one of the strongest risk factors for mental and physical decline, but its mechanisms remain largely unknown. This work seeks to understand: the underlying physiological mechanisms in order to guide both behavioral and pharmacological efforts to prevent disease and promote health in the elderly.