Integrin Functions in Shaping Cortical Circuits

项目摘要 这位候选人是詹姆斯麦迪逊大学的终身助理教授，他的首要目标是 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阐明发育和细胞- 整合素在大脑中的特定作用，他的建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（Itgb 3）在发育、解剖、生理和行为中的作用， 兴奋性皮层回路的研究他的职业目标是建立研究的独立性， 优秀的同事网络。实现这些目标也将加强他的研究计划， NINDS相关领域成功竞争R 01/R15资金，并获得终身职位。一 由NIH资助的优秀导师团队将指导候选人实现既定目标。主 导师是马克加布里埃尔博士（詹姆斯麦迪逊大学），发育神经生物学专家这三个共同- 导师是神经科学家乔纳森·基普尼斯博士（弗吉尼亚大学），自闭症和神经免疫学专家， Patricia Maness（Patricia Maness）是神经发育障碍相关细胞粘附分子方面的专家， Gregorio巴尔德斯博士（弗吉尼亚理工大学），最近NINDS K 01获奖者谁已经获得了R 01， 任职候选人得到了同事（职业咨询委员会）和机构的全力支持。 这项研究的总体目标是了解Itgb 3在兴奋性脑损伤中的发育作用。 在体内皮层电路，并建立一个框架，连接解剖，生理和行为 Itgb 3功能丧失的后果。核心假设是，在关键时期需要Itgb 3 用于限制锥体神经元中树突的发育，建立锥体神经元中所需的正常兴奋性音调， 正常社交行为的前额叶皮层初步数据支持这一假设，将由 追求3个目标：（目标1）确定Itgb 3是否介导兴奋性皮质内的树突发育 锥体神经元，在前额皮质建立正常社会行为的神经基质。(Aim（二） 定义Itgb 3功能在前额叶皮层兴奋性皮质锥体神经元的关键时期。(Aim第三章 定义Itgb 3在前额叶皮质兴奋性皮质锥体神经元中的突触功能。这 这一贡献是重要的，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，因为它将目前的研究转向了神经元和皮层， 通过在发育过程中体内引起Itgb 3功能的细胞类型特异性丧失，来抑制Itgb 3的特异性功能。 总的来说，候选人在执行一项 研究和职业计划，这将导致他朝着他的目标，揭示了整合素β 3在皮质 发展，并建立一个积极的研究计划，将揭示基本知识， 大脑和神经系统，以减少神经发育障碍，如自闭症的负担。

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.