Role of Corticosterone on Hippocampal Cell Proliferation in Mice with Diabetes

皮质酮对糖尿病小鼠海马细胞增殖的作用

基本信息

批准号：
7868045
负责人：
Nancy Ho
金额：
$ 3.01万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2011-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The applicant seeks a training opportunity that will prepare her to successfully engage in research that elucidates aspects of the relationship between mental and physical health. The concept of mind-body interaction recognizes that mental and physical health influence one another, although the mechanisms responsible for these influences are still unknown. The applicant will use a rodent model of diabetes induced by the drug streptozotocin (STZ), to examine how a physical condition might precipitate affective and neurological changes. Studies directed at determining the underlying neurobiological alterations occurring during diabetes will lead to better predictors of risk as well as identifying rational targets of new therapies to manage biobehavioral complications of this common disease. The effect of diabetes on neural function will be evaluated through behavioral tests and measurement of hippocampal neurogenesis. The core hypothesis of this proposal is that reduced neurogenesis resulting from diabetes is produced, in whole or in part, by dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis with concomitant elevations of the hormone corticosterone (CORT). Suppression of hippocampal neurogenesis, known to result from persistent CORT elevations, may be associated with increased vulnerability to depression and cognitive deficits. The mechanism underlying suppressed neurogenesis in diabetes models is not known. However, it is known that increased CORT decreases neurogenesis, and diabetes models are associated with increased levels of circulating CORT. Using a 2x2 factorial design, this study will determine whether diabetes-related CORT elevation mediates changes in behavior and/or neurogenesis. If the results obtained in this study support the hypothesis that HPA axis dysregulation and excess CORT contribute to diabetesrelated suppression of hippocampal cell proliferation, and if controlling CORT levels restores neurogenesis and improves behavioral and cognitive deficits, then a new pharmacologic target will have been identified. This will be an innovative avenue of investigation with a potential pathway that leads to brain-related diabetic complications. Manipulation of this pathway may increase the quality of life of patients suffering from diabetes through preserving cognitive function and limiting psychological and mood alterations. This proposed training will take place at the University of Pennsylvania under the mentorship of Drs. Nancy Tkacs and Irwin Lucki. During this fellowship, the applicant will develop and conduct an innovative program of neuroscience research that will identify pharmacological targets and ways to improve the quality of life of those with diabetes and comorbid neurologically based complications.

描述（由申请人提供）：申请人寻求培训机会，使她能够成功地进行研究，从而阐明心理和身体健康之间关系的各个方面。心身互动的概念认识到身心健康相互影响，尽管对这些影响的造成的机制仍然未知。申请人将使用由药物链球菌素（STZ）诱导的啮齿动物模型来检查物理状况如何沉淀情感和神经系统变化。旨在确定糖尿病期间发生的潜在神经生物学改变的研究将导致更好的风险预测指标，并确定新疗法的合理靶标，以管理这种常见疾病的生物行为并发症。糖尿病对神经功能的影响将通过行为测试和海马神经发生的测量来评估。该提案的核心假设是，通过下丘脑 - 垂体 - 肾上腺肾上腺（HPA）轴的失调，导致糖尿病引起的神经发生减少，并伴有激素皮质酮（Cort）的升高。抑制海马神经发生，已知是由持续的Cort升高引起的，可能与增加抑郁症和认知缺陷的脆弱性有关。糖尿病模型中抑制神经发生的基础机制尚不清楚。然而，众所周知，Cort增加会降低神经发生，糖尿病模型与循环Cort水平升高有关。使用2x2阶乘设计，这项研究将确定与糖尿病相关的Cort升高是否介导行为和/或神经发生的变化。如果本研究中获得的结果支持HPA轴失调和过量CORT的假设有助于糖尿病相关的海马细胞增殖抑制，并且如果控制CORT水平可以恢复行为和认知缺陷，那么将确定新的药理靶标。这将是一种创新的调查途径，并具有潜在的途径，导致与大脑有关的糖尿病并发症。操纵这一途径可能会通过保留认知功能并限制心理和情绪改变来提高患有糖尿病患者的生活质量。这项拟议的培训将在宾夕法尼亚大学的指导下在宾夕法尼亚大学进行。南希·塔克斯（Nancy Tkacs）和欧文·卢西（Irwin Lucki）。在此奖学金期间，申请人将开发和开展一项创新的神经科学研究计划，该计划将确定药理目标和方法，以改善糖尿病和基于神经学的并发症患者的生活质量。