Investigating the role of astrocytes on neuronal activity and behavioral modulation

项目摘要/摘要： 本提案描述了一个为期四年的培训项目，该项目将使申请者为实现目标做好准备。 成为糖尿病和神经生物学研究的独立研究员。在这里提出的这项研究 旨在更好地了解大脑中的胰岛素和IGF-1信号，这将对 公共卫生。申请者还提出了详细的培训计划，其中包括在专业领域的进一步培训 技术和参加科学和职业发展研讨会和课程。申请人有 组建了一支优秀的波士顿指导团队，为研究和职业生涯提供支持 在整个培训期间的发展。申请者将由C.Ronald Kahn博士共同指导， 哈佛医学院乔斯林糖尿病中心著名胰岛素信号和糖尿病研究专家 以及塔夫茨大学星形胶质细胞生物学和神经胶质传递方面的先驱和专家菲利普·海登博士 大学医学院。此外，申请者将从以下机构获得技术和智力支持 科学顾问伊曼纽尔·波托斯博士和布拉德福德·洛厄尔博士。 众所周知，胰岛素在大脑中起作用，抑制食欲，改善认知和抑郁。 症状。糖尿病患者患神经疾病的风险更大，包括阿尔茨海默氏症 疾病和严重的抑郁症。大脑中胰岛素受体的丧失会导致过量进食，胰岛素抵抗 在小鼠身上表现出更多类似抑郁的行为。所有这些都表明，胰岛素是一种需要维持的关键调节因子 正常的神经生理学。然而，大脑中胰岛素信号控制的机制 神经行为仍然没有被完全理解。我的初步研究表明，具有星形胶质细胞特异性的小鼠 胰岛素受体缺失表现出抑郁样行为增加，这表明胰岛素信号 星形胶质细胞起源于星形胶质细胞，对神经元活动和行为的调节具有重要意义。的总目标是 本研究旨在研究胰岛素受体(IR)和胰岛素样生长因子-1受体(IGF1R)在星形胶质细胞中的相对作用 神经功能和行为。中心假设是IR，可能还有IGF1R，信号是 对星形胶质细胞的正常新陈代谢和功能很重要，这些活动的丧失将导致改变 神经递质稳态，它第二次调节多巴胺能神经元的活动，从而改变 行为。目标1将确定IR和IGF1R在星形胶质细胞中对 细胞内信号、细胞代谢、神经递质释放，这些都可能有助于神经元 监管。目的2将研究IR和IGF1R在星形胶质细胞中对多巴胺能神经回路和 在正常和糖尿病情况下的情绪调节。这些研究将扩大我们对IR和IGF1R的了解 在正常生理条件下以及糖尿病和胰岛素的情况下大脑中的信号 这种药物具有抗药性，可为糖尿病和许多其他疾病的预防和治疗提供新的途径。

Project Summary/Abstract: This proposal describes a four-year training project, which will prepare the applicant to achieve the goal of becoming an independent investigator in diabetes and neurobiology research. The research proposed here aims to better understand insulin and IGF-1 signaling in the brain, which will have potential implications for public health. The applicant also proposes a detailed training plan, which includes further training in specialized techniques and attending scientific and career development seminars and courses. The applicant has assembled an outstanding Boston-based mentoring team to support the research as well as career development throughout the training period. The applicant will be co-mentored by Dr. C. Ronald Kahn, a renowned expert in insulin signaling and diabetes research, at Joslin Diabetes Center, Harvard Medical School, and Dr. Philip Haydon, a pioneer and expert in astrocyte biology and gliotransmission, at Tufts University College of Medicine. In addition, the applicant will receive technical and intellectual support from scientific advisors Drs. Emmanuel Pothos and Bradford Lowell. Insulin is known to act in the brain to suppress appetite and to improve cognition and depression symptoms. Patients with diabetes have a greater risk to develop neurological disorders, including Alzheimer's disease and major depression. Loss of insulin receptors in the brain leads to overfeeding, insulin resistance and more depressive-like behaviors in mice. All of these indicate that insulin is a key regulator to maintain normal neurophysiology. However, the mechanism by which insulin signaling in the brain controls neurobehaviors is still not fully understood. My preliminary studies show that mice with astrocyte-specific insulin receptor deletion exhibit increased depressive-like behavior, which indicates that insulin signaling originated from astrocytes is important for regulation of neuronal activity and behaviors. The overall goal of this project is to characterize the relative roles of insulin receptor (IR) and IGF-1 receptor (IGF1R) in astrocytes for neural functions and behaviors. The central hypothesis is that IR, and possibly IGF1R, signaling is important for normal metabolism and function of astrocytes, and that loss of these actions will lead to altered neurotransmitter homeostasis, which secondarily modulates dopaminergic neuronal activity, thus altering behaviors. Aim 1 will define the cell autonomous roles of IR and IGF1R in astrocytes on the regulation of intracellular signaling, cellular metabolism, neurotransmitter release, which could contribute to neuronal regulation. Aim 2 will examine the roles of IR and IGF1R in astrocytes on dopaminergic neural circuitry and mood regulation in normal and diabetic conditions. These studies will expand our knowledge of IR and IGF1R signaling in the brain under normal physiological condition and in the context of diabetes and insulin resistance, and could provide new avenue for prevention and therapy of diabetes and many other disorders.