Integrin Functions in Shaping Cortical Circuits

整合素在塑造皮质回路中的功能

• 批准号: 9976641
• 负责人: George Vidal
• 金额: $ 21.06万
• 依托单位: JAMES MADISON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976641
• 关键词: Advisory Committees; Affect; Age; American; Anatomy; Area; Award; Axon; Behavior; Behavioral; Binding; Brain; Cell Adhesion Molecules; Cell physiology; Cells; Cerebral cortex; Cerebrum; Child; Data; Dendrites; Dendritic Spines; Development; Diagnosis; Disease; Electrophysiology (science); Embryo; Equilibrium; Event; Extracellular Matrix; Foundations; Funding; Goals; Growth; ITGB3 gene; In Vitro; Institution; Integrin beta Chains; Integrins; Intellectual functioning disability; Knock-out; Knowledge; Lead; Link; Mediating; Mentors; Mentorship; Morphology; Mus; Mutation; National Institute of Neurological Disorders and Stroke; Neurites; Neurodevelopmental Disorder; Neuroglia; Neurons; Physiological; Positioning Attribute; Prefrontal Cortex; Process; Public Health; Research; Role; Secure; Shapes; Social Behavior; Structure; Susceptibility Gene; Synaptic Transmission; Telencephalon; Testing; Time; United States National Institutes of Health; Universities; Virginia; autism spectrum disorder; autistic behaviour; base; career; cell motility; cell type; conditional knockout; critical period; density; design; developmental neurobiology; excitatory neuron; gene function; hippocampal pyramidal neuron; in vivo; innovation; loss of function; migration; neuroimmunology; neuronal circuitry; postnatal; professor; programs; reconstruction; relating to nervous system; synaptic function; tenure track; treatment strategy

PROJECT SUMMARY The candidate is a tenure-track assistant professor at James Madison University, with the overarching goal of understanding the development of the structure and function of the cerebral cortex to better diagnose and treat neurodevelopmental disorders. His long-term research objective is to clarify the developmental and cell- specific roles of integrins in the brain, and the overall focus of his proposal is to advance this objective by understanding the developmental, anatomical, physiological, and behavioral roles of integrin beta 3 (Itgb3) in excitatory cortical circuitry in vivo. His professional goals are to establish research independence and create a network of outstanding colleagues. Achieving these goals will also strengthen his research program in a NINDS-relevant area to compete successfully for R01/R15 funding by year 3 of the award and achieve tenure. A team of outstanding, NIH-funded mentors will guide the candidate toward the stated goals. The primary mentor is Dr. Mark Gabriele (James Madison Univ.), an expert in developmental neurobiology. The three co- mentors are neuroscientists Dr. Jonathan Kipnis (UVA), an expert in autism and neuroimmunology, Dr. Patricia Maness (UNC), an expert in cell adhesion molecules associated with neurodevelopmental disorders, and Dr. Gregorio Valdez (Virginia Tech), a recent NINDS K01 awardee who has since secured an R01 and tenure. The candidate has the full support of his colleagues (Career Advisory Committee) and institution. The overall goal of the proposed research is to understand the developmental role of Itgb3 in excitatory cortical circuitry in vivo and establish a framework linking the anatomical, physiological, and behavioral consequences of Itgb3 loss of function. The central hypothesis is that Itgb3 is required during a critical period for restricting dendritic development in pyramidal neurons, establishing a normal excitatory tone required in prefrontal cortex for normal social behavior. Preliminary data support this hypothesis, which will be tested by pursuing 3 aims: (Aim 1) Determine if Itgb3 mediates dendritic development within excitatory cortical pyramidal neurons, establishing a neural substrate for normal social behavior in prefrontal cortex. (Aim 2) Define a critical period for Itgb3 function in excitatory cortical pyramidal neurons of prefrontal cortex. (Aim 3) Define synaptic functions of Itgb3 in excitatory cortical pyramidal neurons of prefrontal cortex. This contribution is significant because it will be the first to provide a mechanism for in vivo neuronal function of integrin beta 3. The research is innovative because it shifts current research toward the neuron- and cortex- specific functions of Itgb3 by causing cell-type-specific loss of function of Itgb3 in vivo during development. Taken together, the candidate has the full support of his mentors and institution as he executes a research and career plan that will lead him toward his goals of uncovering a role for integrin beta 3 in cortical development, and of establishing an active research program that will uncover fundamental knowledge about the brain and nervous system to reduce the burden of neurodevelopmental disorders such as autism.

项目摘要 候选人是詹姆斯·麦迪逊大学的终身助理助理教授，其总体目标是 了解大脑皮层的结构和功能的发展，以更好地诊断和治疗 神经发育障碍。他的长期研究目标是澄清发育和细胞 整合素在大脑中的具体作用，以及他的提议的总体重点是通过 了解整联蛋白β3（ITGB3）在 体内兴奋性皮质回路。他的职业目标是建立研究独立性并创建一个 杰出同事网络。实现这些目标也将加强他的研究计划 与Ninds相关的地区将在该奖项的第3年获得成功的R01/R15资金，并取得任期。一个 由NIH资助的导师组成的团队将指导候选人实现既定目标。主要 导师是发展神经生物学专家Mark Gabriele博士（James Madison Univ。）。这三个共同 导师是神经科学家Jonathan Kipnis博士（UVA），自闭症和神经免疫学专家，博士。 Patricia Maness（UNC），与神经发育疾病相关的细胞粘附分子专家 Gregorio Valdez博士（Virginia Tech）是最近的Ninds K01获奖者，此后获得了R01和 任期。候选人得到了他的同事（职业咨询委员会）和机构的全部支持。 拟议研究的总体目标是了解ITGB3在兴奋性中的发展作用 体内皮质电路并建立一个连接解剖，生理和行为的框架 ITGB3功能丧失的后果。中心假设是在关键时期需要ITGB3 为了限制锥体神经元中的树突状发展，建立了正常的兴奋性语调 正常社会行为的前额叶皮层。初步数据支持此假设，该假设将通过 追求3个目标：（目标1）确定ITGB3是否介导了兴奋性皮质中的树突发展 锥体神经元，为前额叶皮层中的正常社会行为建立神经底物。 （目标2） 定义在额叶皮层的兴奋性皮质金字塔神经元中ITGB3功能的关键时期。 （目标3） 定义ITGB3在前额叶皮层的兴奋性皮质锥体神经元中的突触功能。这 贡献很重要，因为它将是第一个提供体内神经元功能机制的贡献 整合蛋白β3。这项研究具有创新性，因为它将当前的研究转移到神经元和皮层 - ITGB3的特定功能是通过在开发过程中引起体内ITGB3功能特异性功能的特定功能。 综上所述，候选人得到了导师和机构的全部支持 研究和职业计划将使他朝着揭示Cortical中整合素Beta 3角色的目标 开发以及建立一个积极的研究计划，该计划将发现有关的基本知识 大脑和神经系统减轻了自闭症等神经发育障碍的负担。