Intracellular signaling in the development of human cognitive function

人类认知功能发育中的细胞内信号传导

• 批准号: 8641713
• 负责人: M. CHIARA MANZINI
• 金额: $ 21.02万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8641713
• 关键词: Affect; Award; Behavioral; Binding; Biological; Boston; Brain; Child; Cognitive; Coiled-Coil Domain; Complex; Cytoskeletal Modeling; Data; Defect; Dendrites; Dendritic Spines; Development; Dimerization; Disability phenotype; Disease; Electrophysiology (science); Electroporation; Enhancers; Etiology; Excitatory Synapse; Faculty; Family; Family member; Fragile X Syndrome; Funding; Future; Genes; Genetic; Genetic Transcription; Goals; Healthcare Systems; Human; Human Development; Impaired cognition; Inherited; Inhibitory Synapse; Intellectual functioning disability; Laboratories; Lead; Learning; Life; Mass Spectrum Analysis; Measures; Mediating; Memory; Mentors; Modeling; Molecular; Molecular Target; Morphology; Mus; Neurites; Neurologic; Neuronal Differentiation; Neurons; Pathogenesis; Pathway interactions; Patients; Personal Communication; Phase; Phenotype; Population; Positioning Attribute; Protein Family; Proteins; Research; Research Personnel; Role; Scaffolding Protein; Secure; Self Care; Signal Pathway; Signal Transduction; Signaling Protein; Societies; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Training; Transduction Gene; Work; abstracting; base; career; career development; cognitive function; immunocytochemistry; improved; in utero; loss of function; loss of function mutation; mouse model; novel; null mutation; paralogous gene; patch clamp; protein function; receptor; skills; synaptic function; synaptogenesis; therapeutic target; tool

7. Project Summary/Abstract 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 enourmous 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 knowk cause of ID in humans. The Mentored phase of the award is to be conducted at Children's Hopital 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.

7. 项目总结/摘要 智力障碍 (ID)，即智力功能下降和日常生活技能受限，例如 个人护理和沟通，影响了多达 2% 的美国人口，并给人们带来了巨大的负担 家庭、医疗保健系统和社会。此 K99/R00 提案旨在支持职业生涯 M. Chiara Manzini 博士在探索 ID 背后的分子机制时通过研究 信号基因 CC2D1A，这是人类 ID 的已知原因。该奖项的指导阶段是 在 Christopher Walsh 博士的指导下在波士顿儿童医院进行，该项目将在 在获得独立教职职位后，曼齐尼博士继续在自己的实验室工作。 Manzini 博士的初步工作明确证实 CC2D1A 功能缺失突变是导致严重疾病的原因之一。 人类非综合征性 ID，表明小鼠神经元中 Cc2d1a 功能的扰动会导致 神经元形态的变化和树突棘数量的减少。形态和突触 众所周知，神经元的缺陷与学习和记忆的行为缺陷有关，而这的最初部分 提案（将在奖励的指导阶段进行）将确定 CC2D1A 的损失如何 功能可能导致认知障碍。具体目标 1 将调查形态缺陷如何 观察到 Cc2d1a 敲低后会影响突触接触的形成和功能。具体目标2 将探索 Cc2d1a 功能丧失时观察到的表型背后的分子机制。 Cc2d1a 敲除增加了 NF-¿B 的转录活性，NF-¿B 是树突生长的重要调节因子 突触可塑性和特定目标 2 将测试 NF-¿B 活性是否以及如何参与 Cc2d1a 功能丧失的形态和功能表型。 具体目标 3（将在 Manzini 博士的实验室完成）将进一步探索 Cc2d1a 的生物学作用 研究其哺乳动物旁系同源物 Cc2d1b。我们对 Cc2d1a 进行质谱分析的初步数据 结合伙伴表明，Cc2d1b 是与 Cc2d1a 结合的最常见蛋白质之一 我们假设这些蛋白质在大脑中发挥着复杂的作用，并且可能具有多余的作用。因此， 为了了解 Cc2d1a 的信号传导活性及其在 ID 发病机制中的作用，我们需要研究 Cc2d1 家族成员的相互作用和功能的综合丧失。 曼齐尼博士作为独立研究者的长期职业目标是概述信号通路 参与认知功能的发展并继续研究智力障碍的遗传原因，希望 鉴定与疾病病因有关的其他信号蛋白。这个奖项将帮助她 完成她的培训并提供一个跳板来获取成功的 R01 申请资助她的数据 未来的工作。