NEURAL RESPONSE TO INSULIN RESISTANCE TREATMENTS

说明（由申请人提供）：这是一份申请辅导病人导向职业发展奖（K23）的申请。该奖项将为申请人提供所需的高级技能，以建立一个使用神经成像和神经心理学方法研究肥胖和代谢功能障碍的独立项目。拟议的研究将使用功能磁共振成像、代谢功能的生物标志物和神经心理学测试来检查接受胰岛素抵抗治疗的肥胖和久坐的中年人的认知和大脑反应的变化。我们将招募75名肥胖参与者，他们正在华盛顿大学医学院营养与肥胖研究中心参加一项现有的减肥研究。参与者将被随机分配到三种情况之一：1)6个月的口服噻唑烷二酮类药物（吡格列酮）治疗，以增加胰岛素敏感性（n=25）；2) 6个月的标准化减肥干预，达到8-10%的体重减轻并增加胰岛素敏感性（n=25）；3)在正常饮食和体重维持后6个月的等候名单对照组（n=25）。在基线和随访时，所有参与者将完成葡萄糖钳测试、身体成分评估、血液测试、血压检查、综合心理测量评估、简短精神评估、身体活动问卷调查和结构和功能MRI。本研究的目的是：1)确定神经心理表现是否会随着胰岛素敏感性的提高而改善；2)确定对胰岛素敏感性的提高是否会导致fMRI脑反应测量的神经效率的提高。申请人提出一个综合的培训计划，将教学指导与现有的研究人员相结合；正式课程，包括完成临床研究硕士学位；参加若干高级讲习班；参加华盛顿大学医学院正在进行的研讨会，包括营养和肥胖研究研讨会，奈特阿尔茨海默病研究中心；并与个别导师一起应用培训经验。具体的培训目标包括神经成像方法的高级知识和技能获取，包括基于任务的功能磁共振成像，功能磁共振成像的纵向方法，以及结构MRI皮层重建技术。还将通过课程和参加讲习班提供高级统计建模方法方面的培训。额外的课程将在营养学、代谢学、内分泌学、多模态神经影像学和负责任的研究中完成。本提案的总体研究目标是验证通过减肥或噻唑烷二酮治疗改善胰岛素敏感性的假设，并伴随着认知表现和fMRI脑反应的有益变化。

DESCRIPTION (provided by applicant): This is an application for a Mentored Patient-Oriented Career Development Award (K23). This award will provide the Applicant with advanced skills needed to establish an independent program of research in obesity and metabolic dysfunction using neuroimaging and neuropsychological methodologies. The proposed study will use fMRI, biomarkers of metabolic functioning, and neuropsychological tests to examine changes in cognition and brain response in obese and sedentary middle aged adults undergoing treatment for insulin resistance. We will enroll 75 obese participants who are participating in an existing study of weight reduction at the Nutrition and Obesity Research Center at Washington University Medical School. The participants will be randomly assigned to one of three conditions: 1) Six months of treatment with an oral thiazolidinedione medication (pioglitazone) to increase insulin sensitivity (n=25); 2) Six months of a standardized weight reduction intervention to achieve an 8-10% weight reduction and increased insulin sensitivity (n=25); or 3) A wait-list control group following 6 months of usual diet and weight maintenance (n=25). At baseline and follow- up, all participants will complete glucose clamp testing, body composition assessment, blood tests, blood pressure checks, comprehensive psychometric assessment, brief psychiatric assessment, physical activity questionnaires, and structural and functional MRI. The aims of the study are: 1) To determine if neuropsychological performance will improve as a function of increased insulin sensitivity and 2) To determine whether improved sensitivity to insulin will result in increased neural efficiency as measured by fMRI brain response. The Applicant proposes a comprehensive training plan, combining didactic instruction with established researchers; formal coursework including completion of a Master's Degree in Clinical Investigation; participation in several advanced workshops; participation in ongoing seminars at Washington University Medical School including the Nutrition and Obesity Research Seminar, the Knight Alzheimer's Disease Research Center; and applied training experiences with individual mentors. Specific training goals include advanced knowledge and skill acquisition in neuroimaging methodologies, including task-based fMRI, longitudinal approaches in fMRI, and structural MRI cortical reconstruction techniques. Training in advanced statistical modeling methodologies will also be provided by coursework and workshop participation. Additional coursework will be completed in nutrition, metabolism, endocrinology, multimodal neuroimaging, and the responsible conduct of research. The overall research goal of this proposal is to test the hypothesis that improved insulin sensitivity achieved through weight reduction or thiazolidinedione treatment is accompanied by beneficial changes in cognitive performance and fMRI brain response.