Investigating the role of astrocytes on neuronal activity and behavioral modulation

研究星形胶质细胞对神经元活动和行为调节的作用

• 批准号: 10099014
• 负责人: Weikang Cai
• 金额: $ 14.3万
• 依托单位: NEW YORK INST OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-26 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10099014
• 关键词: Alzheimer' s Disease; Alzheimer' s disease risk; Anxiety; Astrocytes; Attention; Behavior; Behavioral; Biological Process; Biology; Boston; Brain; Cells; Cognition; Data; Defect; Desire for food; Diabetes Mellitus; Disease; Dopamine; Eating; Exhibits; Exocytosis; Gene Expression; Glutamates; Goals; High Fat Diet; Homeostasis; Human; Hypoglycemia; Hypogonadism; Hypothalamic structure; Impairment; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Intranasal Administration; Knock-out; Knockout Mice; Knowledge; Link; Major Depressive Disorder; Mediating; Medicine; Mental Depression; Mentors; Metabolic; Metabolism; Mood Disorders; Moods; Mus; Neuraxis; Neurobiology; Neurons; Neurophysiology - biologic function; Neurotransmitters; Nucleus Accumbens; Nutrient; Patients; Physiological; Play; Prevention therapy; Public Health; Receptor Signaling; Regulation; Research; Research Personnel; Research Support; Risk; Rodent; Role; Serine; Signal Transduction; Synapses; System; Techniques; Training; Type 2 diabetic; Universities; base; career development; college; depressive symptoms; diabetes mellitus therapy; diabetic; diabetic patient; dopaminergic neuron; improved; in vivo; insight; insulin signaling; medical schools; mind control; mood regulation; mood symptom; nervous system disorder; neural circuit; neurobehavior; neuronal circuitry; neurophysiology; neurotransmitter release; receptor function; receptor-mediated signaling; response; training project; type I diabetic

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.

项目概要/摘要： 本建议书描述了一个为期四年的培训项目，该项目将为申请人实现目标做好准备 成为糖尿病和神经生物学研究的独立研究者。这里提出的研究 旨在更好地了解胰岛素和IGF-1在大脑中的信号传导，这将对 公共卫生申请人还提出了一份详细的培训计划，其中包括进一步培训专门 技术和参加科学和职业发展研讨会和课程。申请人已经 组建了一支优秀的波士顿指导团队，以支持研究和职业生涯 在整个培训过程中。申请人将由C博士共同指导。罗纳德卡恩a 他是哈佛医学院乔斯林糖尿病中心胰岛素信号和糖尿病研究领域的著名专家 菲利普·海顿博士是塔夫茨大学星形胶质细胞生物学和胶质细胞传递的先驱和专家， 大学医学院。此外，申请人还将获得以下方面的技术和智力支持： 科学顾问Emmanuel Pothos博士和Bradford Lowell博士 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系统疾病的风险更大，包括阿尔茨海默氏症 疾病和严重抑郁症。大脑中胰岛素受体的缺失会导致过度进食，胰岛素抵抗 和更多类似抑郁的行为。所有这些都表明，胰岛素是维持 正常的神经生理学。然而，大脑中的胰岛素信号控制 神经行为仍然没有完全被理解。我的初步研究表明， 胰岛素受体缺失表现出增加的抑郁样行为，这表明胰岛素信号传导 起源于星形胶质细胞的神经胶质细胞对于调节神经元活动和行为是重要的。的总目标 该项目旨在表征胰岛素受体（IR）和IGF-1受体（IGF 1 R）在星形胶质细胞中的相对作用 神经功能和行为。核心假设是IR，可能还有IGF 1 R，信号传导是 对于星形胶质细胞正常代谢和功能是重要的，这些作用的丧失将导致改变 神经递质稳态，其次级调节多巴胺能神经元活性，从而改变 行为。目的1将明确IR和IGF 1 R在星形胶质细胞中对细胞增殖的调控中的细胞自主作用， 细胞内信号传导，细胞代谢，神经递质释放，这可能有助于神经元 调控目的2将研究IR和IGF 1 R在星形胶质细胞中对多巴胺能神经回路的作用， 正常和糖尿病状态下的情绪调节。这些研究将扩大我们对IR和IGF 1 R的认识 在正常生理条件下以及在糖尿病和胰岛素的背景下， 耐药性，并可能为预防和治疗糖尿病和许多其他疾病提供新的途径。