EFFECT OF GLUCOCORTICOIDS ON MAMMALIAN TOLLOID-EXPRESSION IN THE HIPPOCAMPUS

糖皮质激素对哺乳动物海马 Tolloid 表达的影响

• 批准号: 7959610
• 负责人: TIMOTHY G CLARK
• 金额: $ 10.89万
• 依托单位: UNIVERSITY OF SOUTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959610
• 关键词: Ablation; Adaptive Behaviors; Adrenal Cortex; Adult; Affect; Animals; Bone Morphogenetic Proteins; Borderline Personality Disorder; Cells; Chronic stress; Computer Retrieval of Information on Scientific Projects Database; Corticosterone; Dendritic Spines; Disease; Environment; Funding; Gene Expression; Glucocorticoid Receptor; Glucocorticoids; Grant; Hippocampus (Brain); Homeostasis; Institution; Mammals; Mediating; Metalloproteases; Neurons; Organism; Parahippocampal Gyrus; Post-Traumatic Stress Disorders; Research; Research Personnel; Resources; Response Elements; Schizophrenia; Source; Stimulus; Stress; Stressful Event; Tissues; United States National Institutes of Health; axon growth; base; biological adaptation to stress; cell type; dentate gyrus; hypothalamic-pituitary-adrenal axis; mRNA Expression; neurogenesis; neuromechanism; promoter; synaptogenesis

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The ability of an organism to adapt to changes in its environment to maintain homeostasis is critical for survival. A threat to this homeostasis results in stress and successful adaptation to counter the effects of stress confers a survival advantage. The stress response is mediated, in part, by the hypothalamic-pituitary-adrenal (HPA) axis. Stimulation of the HPA axis by a stressful event results in the secretion of glucocorticoids from the adrenal cortex. Glucocorticoids affect a variety of tissues to enable the organism to adapt to the stress. Hippocampal neurons contain glucocorticoid receptors and respond to elevated glucocorticoid levels by downregulating the HPA axis. Chronically stress, however, is deleterious to hippocampal neurons. Chronically elevated levels of glucocorticoids result in a decrease in the number of dendritic spines, reduced axonal growth and synaptogenesis and decreased neurogenesis in the hippocampus. These changes may be the basis for diseases and disorders attributed to chronic stress, such as Post Traumatic Stress Disorder, Borderline Personality Disorder and Schizophrenia. Mammalian Tolloid-like 1 (mTll-1) is a metalloprotease that potentiates the activity of the Bone Morphogenetic Proteins (BMPs). BMPs are required for neurogenesis in the hippocampus of both developing and adult mammals. In the promoter of mTll-1 there are 2 putative glucocorticoid response element indicating that mTll-1 may be regulated by glucocorticoids. mTll-1 is expressed by a small subset of cells that increase in animals with enhanced neurogenesis. This proposal seeks to determine if mTll-1 expression is responsive to the levels of circulating glucocorticoids. The first aim will be to determine the cell type that expresses mTll-1. Secondly, does stressful stimuli result in changes in mTll-1 mRNA expression. Third, does the administration of exogenous glucocorticoids (corticosterone) result in changes in mTll-1 mRNA expression in a fashion similar to that of stressful stimuli. Finally, does the ablation of mTll-1 gene expression change the rate of neurogenesis within the dentate gyrus of the hippocampus? The results of these studies will provide a possible mechanism for the effect of chronic stress and elevated glucocorticoid levels on hippocampal function.

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