2008 — 2011 |
Gillespie, Charles Frederick |
K23Activity Code Description: To provide support for the career development of investigators who have made a commitment of focus their research endeavors on patient-oriented research. This mechanism provides support for a 3 year minimum up to 5 year period of supervised study and research for clinically trained professionals who have the potential to develop into productive, clinical investigators. |
Trauma and the Genetics of the Endocannabinoid System
[unreadable] DESCRIPTION (provided by applicant): Post-traumatic stress disorder (PTSD) is a prevalent and debilitating syndrome that occurs in some, but not all, individuals exposed to traumatic events. Acquisition of PTSD is contingent on psychological as well as genetic factors. Several lines of research suggest that the endocannabinoid system of neurotransmitters may have a role in the etiology of PTSD through effects on the neural systems involved in fear learning and motivation. We hypothesize that in trauma-exposed individuals, variants of endocannabinoid genes are associated with altered risk for PTSD. This project will investigate a system of seven major genes important for function of the endocannabinoid system. Because endocannabinoids are rapidly synthesized on demand and metabolized, functional changes within synthesizing/metabolizing enzymes or receptors may have [unreadable] signaling consequences. Such consequences may be reflected in risk for psychiatric illness. We will examine genes involved in the synthesis of endocannabinoids [NAPE-PLD (N-arachidonoyl phosphatidylethanolamine-hydrolyzing Phospholipase D), C11orf11 (chromosome 11 open reading frame 11 aka diacylglycerol lipase-alpha), PTPN22 (protein tyrosine phosphatase, non-receptor type 22)]; response to endocannabinoids [CNR1 (cannabinoid receptor 1 aka CB1), CNR2 (cannabinoid receptor 2 aka CB2)], and degradation of endocannabinoids [FAAH (fatty acid amide hydrolase), MGLL (monoglyceride lipase)]-referred to collectively hereafter as "endocannabinoid system genes" (ESGs). We will perform this analysis in a heavily traumatized sample of over 1000 subjects (predominantly African-American) recruited from an inner-city general medical clinic. This project will test the hypothesis that polymorphisms of the ESGs are associated with differential risk for PTSD diagnosis and symptom severity. [unreadable] [unreadable] [unreadable] [unreadable]
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2013 — 2017 |
Gillespie, Charles Frederick |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Stress-Related Psychobiology and Inflammation in Diabetic African-American Women
DESCRIPTION (provided by applicant): Minority populations are exposed to high levels of trauma and have minimal access to psychiatric and general medical care. The studies proposed in the current application seek to investigate the psychobiological mechanisms responsible for elevated cardiometabolic illness risk in African-American women of lower socioeconomic status (SES) with type 2 diabetes mellitus (T2DM) and trauma-related psychopathology (post- traumatic stress disorder [PTSD] and/or major depressive disorder [MDD]). PTSD in particular, and certain forms of mood and anxiety disorders in general, have been repeatedly associated with dysregulation of the nervous, neuroendocrine, and immune systems that is generally characterized by increased circulating norepinephrine and reduced parasympathetic tone, abnormal secretion of cortisol, and variably elevated systemic inflammation. Quantitative differences in the production of autonomic, neuroendocrine, and inflammatory innate immune mediators of the stress response, distinct from those observed in psychologically healthy subjects, are found in patients with PTSD, MDD, or PTSD/MDD. As a consequence, stress mediators may differentially influence the development and progression of obesity, dyslipidemia, carbohydrate intolerance, and impaired endothelial function in patients affected by PTSD and/or MDD through diagnosis- dependent biological pathways. Although a number of reports suggest a relationship between autonomic, neuroendocrine, and immune factors when attempting to understand the pathophysiological mechanisms linking cardiometabolic illnesses and trauma-related psychiatric disorders, to date no studies have examined in a comprehensive manner the ways by which these systems interact. Accordingly, this project seeks to leverage our extensive experience with a low SES, African-American, primary care population with the well-developed research and recruiting infrastructure of the parent project (MH071537) to test the following three hypotheses in a sample of (N=140) female, African-American primary care patients with T2DM: 1.) Significant differences in measures of autonomic and neuroendocrine function assessed before, during, and after psychosocial stress challenge (Trier Social Stress Test) will be identified between trauma- exposed controls and subjects diagnosed with PTSD, MDD, or PTSD+MDD; 2.) Measurements of autonomic function and neuroendocrine mediators collected before, during, and after psychosocial stress challenge will predict measurements of inflammatory mediators collected before, during, and after the psychosocial stress challenge; 3.) Innate inflammatory mediators collected before, during, and after psychosocial stress challenge will predict differences in standard measures of cardiometabolic function (e.g. glucose tolerance test, flow mediated vasodilatation). Knowledge gained by the experiments proposed in this application will increase our understanding of the psychobiology of stress in women with T2DM and trauma-related psychopathology.
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