Intracellular signaling in the development of human cognitive function

描述（由申请人提供）：智力残疾（ID）即智力功能下降和日常生活技能（如个人护理和沟通）的限制，影响了高达2%的美国人口，给家庭、医疗保健系统和社会带来了巨大的负担。这项K99/R00提案旨在支持M. Chiara Manzini博士的职业发展，因为她通过研究信号基因CC2D1A（人类已知的ID原因）来探索ID的分子机制。该奖项的指导阶段将在Christopher Walsh博士的指导下在波士顿儿童医院进行，该项目将在Manzini博士获得独立教师职位后在她自己的实验室继续进行。Manzini博士的初步工作确定了CC2D1A的功能突变丧失是人类严重的非综合征性ID的原因，并表明小鼠神经元中CC2D1A功能的干扰导致神经元形态的变化和树突棘数量的减少。已知神经元的形态和突触缺陷与学习和记忆的行为缺陷相关，本提案的第一部分（将在奖项的指导阶段进行）将确定CC2D1A功能的丧失如何导致认知障碍。特异性目的1将研究Cc2d1a敲低后观察到的形态学缺陷如何影响突触接触的形成和功能。特异性目标2将探讨在Cc2d1a功能丧失时观察到的表型的分子机制。Cc2d1a敲低可增加NF-？B是树突生长和突触可塑性的重要调节因子，特异性Aim 2将测试NF-？B活性参与Cc2d1a功能丧失的形态和功能表型。Specific Aim 3（将在Manzini博士的实验室完成）将通过研究Cc2d1a在哺乳动物中的类似物Cc2d1b，进一步探索Cc2d1a的生物学作用。我们对Cc2d1a结合伙伴的质谱分析的初步数据表明，Cc2d1b是大脑中与Cc2d1a结合的最常见的蛋白质之一，我们假设这些蛋白质在一个复合体中起作用，可能具有冗余作用。因此，为了了解Cc2d1a的信号活性及其在ID发病机制中的作用，我们需要研究两个Cc2d1家族成员的相互作用和联合功能丧失。作为一名独立研究者，Manzini博士的长期职业目标是概述与认知功能发展有关的信号通路，并继续研究ID的遗传原因，希望能发现与该疾病病因有关的其他信号蛋白。这个奖项将帮助她完成她的培训，并为她成功申请R01提供一个跳板，为她未来的工作提供资金。

DESCRIPTION (provided by applicant): Intellectual disability (ID) namely reduced intellectual functioning and limitations in daily-life skills such as personal care and communication, affects up to 2 % of the US population and poses an enormous burden on families, the healthcare system and society. This K99/R00 proposal is aimed at supporting the career development of Dr. M. Chiara Manzini as she explores the molecular mechanisms underlying ID, by studying the signaling gene CC2D1A, a known cause of ID in humans. The Mentored phase of the award is to be conducted at Children's Hospital Boston under the guidance of Dr. Christopher Walsh and the project is to be continued in Dr. Manzini's own laboratory after she secures an independent faculty position. Dr. Manzini's preliminary work firmly establishes loss of function mutations in CC2D1A as a cause of severe non-syndromic ID in humans and indicates that perturbations of Cc2d1a function in murine neurons lead to changes in neuronal morphology and in a reduction in dendritic spine number. Morphological and synaptic deficits in neurons are known correlates to behavioral defects of learning and memory and the initial part of this proposal (to be conducted during the mentored-phase of the award) will establish how loss of CC2D1A function may lead to cognitive impairment. Specific Aim 1 will investigate how the morphological defects observed following Cc2d1a knockdown affect the formation and function of synaptic contacts. Specific Aim 2 will explore the molecular mechanisms underlying the phenotypes observed upon Cc2d1a loss of function. Cc2d1a knockdown increases the transcriptional activity of NF-?B, an important regulator of dendrite outgrowth and synaptic plasticity and Specific Aim 2 will test whether and how NF-?B activity is involved in the morphological and functional phenotypes of Cc2d1a loss of function. Specific Aim 3 (to be completed in Dr. Manzini's lab) will further explore the biological role of Cc2d1a by also studying its mammalian paralog Cc2d1b. Our preliminary data from mass spectrometry analysis of Cc2d1a binding partners show that Cc2d1b is one of the most common proteins found in conjunction with Cc2d1a in the brain and we hypothesize that these proteins function in a complex and may have redundant roles. Thus, to understand the signaling activity of Cc2d1a and its involvement in the pathogenesis of ID, we need to study the interactions and the combined loss of function of both Cc2d1 family members. Dr. Manzini's long term career goal as an independent investigator is to outline the signaling pathways involved in the development of cognitive function and to continue studying genetic causes of ID, with the hope to identify additional signaling proteins involved in the etiology of the disease. This award will help her complete her training and provide a springboard to obtain data for a successful R01 application to fund her future work. PUBLIC HEALTH RELEVANCE: Intellectual disability (ID) affects up to 2 % of the US population and poses an enormous burden on families, the healthcare system and society. The goal of this proposal is to study the signaling mechanisms underlying ID in order to identify molecular targets for therapies aimed at improving cognitive function.