Integrin Functions in Shaping Cortical Circuits

项目总结 这位候选人是詹姆斯·麦迪逊大学(James Madison University)终身教职助理教授，首要目标是 了解大脑皮层结构和功能的发展，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澄清发育和细胞- 整合素在大脑中的具体作用，他的提案的总体重点是通过 了解整合素β3(ITGB3)在发育、解剖、生理和行为中的作用 活体内兴奋性大脑皮层回路。他的职业目标是建立研究独立性，并创造一个 优秀同事的人脉。实现这些目标还将加强他的研究计划 NINDS-相关领域在获奖第三年前成功竞争R01/R15资金并实现终身教职。一个 由美国国立卫生研究院资助的优秀导师团队将指导候选人朝着既定目标前进。初级阶段 导师是詹姆斯·麦迪逊大学的马克·加布里埃勒博士，他是发育神经生物学的专家。三个共同的- 导师是神经科学家乔纳森·基普尼斯博士(UVA)，自闭症和神经免疫学专家。 帕特里夏·马内斯(UNC)是与神经发育障碍相关的细胞黏附分子专家， Gregorio Valdez博士(弗吉尼亚理工大学)，最近获得NINDS K01奖，自那以来获得了R01和 终身教职。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。 本研究的总体目标是了解ITGB3在兴奋性发育中的作用。 并建立了一个连接解剖、生理和行为的框架 ITGB3功能丧失的后果。中心假设是ITGB3在关键时期是必需的 为了限制锥体神经元的树突发育，建立正常的兴奋性音调 正常社会行为的前额叶皮质。初步数据支持这一假设，将通过以下方式进行检验 追求三个目标：(目标1)确定ITGB3是否在兴奋性皮质内介导树突发育 锥体神经元，为前额叶皮质的正常社会行为建立神经基础。(目标2) 确定前额叶兴奋性皮质锥体神经元ITGB3功能的临界期。(目标3) 明确ITGB3在前额叶兴奋性皮质锥体神经元中的突触功能。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β3。这项研究具有创新性，因为它将当前的研究转向神经元--和皮质-- 在发育过程中，通过导致体内特定细胞类型的ITGB3功能丧失来实现ITGB3的特定功能。 综上所述，候选人在执行 研究和职业规划，将带领他实现他的目标，揭示整合素Beta 3在皮质中的作用 发展，并建立一个积极的研究计划，以揭示关于 大脑和神经系统可以减轻自闭症等神经发育障碍的负担。

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.