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.

项目概要 该候选人是詹姆斯·麦迪逊大学的终身教授助理教授，其总体目标是 了解大脑皮层的结构和功能的发育，以便更好地诊断和治疗 神经发育障碍。他的长期研究目标是阐明发育和细胞- 整合素在大脑中的具体作用，他的提议的总体重点是通过以下方式推进这一目标 了解整合素 β 3 (Itgb3) 在发育、解剖、生理和行为方面的作用 体内兴奋性皮层回路。他的职业目标是建立研究独立性并创建一个 优秀同事网络。实现这些目标也将加强他的研究计划 NINDS 相关领域在该奖项的第 3 年成功竞争 R01/R15 资金并获得终身职位。一个 由 NIH 资助的杰出导师团队将指导候选人实现既定目标。初级 导师是发育神经生物学专家 Mark Gabriele 博士（詹姆斯麦迪逊大学）。三人共同 导师是神经科学家 Jonathan Kipnis 博士（UVA）、自闭症和神经免疫学专家、 Patricia Maness（北卡罗来纳大学）是神经发育障碍相关细胞粘附分子方面的专家， Gregorio Valdez 博士（弗吉尼亚理工大学），最近获得 NINDS K01 奖，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）和机构的全力支持。 拟议研究的总体目标是了解 Itgb3 在兴奋性发育中的作用 体内皮质回路并建立连接解剖学、生理学和行为学的框架 Itgb3 功能丧失的后果。中心假设是关键时期需要Itgb3 用于限制锥体神经元的树突发育，建立正常的兴奋性音调 前额皮质负责正常的社会行为。初步数据支持这一假设，该假设将由 追求 3 个目标：（目标 1）确定 Itgb3 是否介导兴奋性皮质内的树突发育 锥体神经元，为前额皮质正常社会行为建立神经基础。 （目标2） 定义前额皮质兴奋性皮质锥体神经元 Itgb3 功能的关键期。 （目标 3） 定义前额皮质兴奋性皮质锥体神经元中 Itgb3 的突触功能。这 贡献是重大的，因为它将是第一个提供体内神经元功能的机制。 整合素β 3。这项研究具有创新性，因为它将当前的研究转向神经元和皮层 通过在发育过程中引起体内 Itgb3 细胞类型特异性功能丧失来抑制 Itgb3 的特定功能。 总的来说，候选人在执行一项任务时得到了导师和机构的全力支持。 研究和职业计划将引导他实现发现整合素 beta 3 在皮质中的作用的目标 的发展，并建立一个积极的研究计划，以揭示有关的基本知识 大脑和神经系统，以减轻自闭症等神经发育障碍的负担。