NEURODEVELOPMENTAL FUNCTION OF HCFC1

HCFC1 的神经发育功能

基本信息

  • 批准号:
    10541351
  • 负责人:
  • 金额:
    $ 4.14万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-01 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

Project Summary Mutation of HCFC1 causes a multiple congenital anomaly syndrome characterized by inborn errors of cobalamin metabolism, intractable epilepsy, intellectual disability, and motor dysfunction. Despite an implication for HCFC1 in these neurological impairments, a mechanism describing the function of HCFC1 during brain development has not been completely elucidated. HCFC1 encodes for a transcriptional co-factor protein known to regulate cellular proliferation of various progenitor cells including neural precursor cells (NPC). NPCs undergo rapid expansion during early brain development and differentiate into all the major cell types in the brain (i.e. neurons, glia). To begin to elucidate a putative mechanism for HCFC1 in NPC expansion, we created the Co60 allele which introduces a loss of function mutation in the zebrafish hcfc1a ortholog. Through immunohistochemical labeling and cell counts, we demonstrated that heterozygous carriers of the Co60 allele (Co60/+) had increased proliferation of NPCs. We next used transcriptomics of Co60/+ whole brain homogenates to reveal a 14-fold increase in the expression of asxl1, a transcription factor critical for cell proliferation and activation of AKT signaling. We found that inhibition of PI3K, an upstream activator of AKT, in Co60/+ mutants restored asxl1 dependent NPC over proliferation. Moreover, preliminary western blotting and densitometry analysis of our mutants confirm hyperphosphorylation of AKT (Thr308). We next used chromatin immunoprecipitation to confirm a direct binding of human HCFC1 to the zebrafish asxl1 promoter. Together, these findings indirectly link for the first time hcfc1a function and asxl1 expression with AKT activation and NPC proliferation. What remains to be understood is the level of AKT signaling in isolated NPCs derived from hcfc1a mutants and which AKT downstream signaling molecules, like mTOR, regulate proliferation. Completion of this study will help to identify novel molecular pathways that regulate brain development downstream of HCFC1 and pinpoint mechanisms as to how its dysregulation contributes to neurodevelopmental disorders. During the F99 phase of this award, I seek to gain working knowledge of techniques in molecular biology that include protein isolation, western immunoblotting, fluorescence activated cell sorting (FACS), flow cytometry, advanced imaging, and behavioral neuroscience. Additionally, I aim to refine my skills and obtain professional development in grantsmanship, manuscript review and preparation, build and maintain my science network, and finalize my dissertation research.
项目摘要 HCFC1基因突变导致以钴胺先天缺陷为特征的多发性先天性畸形综合征 新陈代谢、顽固性癫痫、智力残疾和运动障碍。尽管对HCFC1有影响 在这些神经损伤中,描述大脑发育过程中HCFC1功能的机制 尚未完全阐明。HCFc1编码一种转录辅助因子蛋白,已知可调节 包括神经前体细胞(NPC)在内的各种祖细胞的细胞增殖。鼻咽癌经历了快速 在大脑发育早期扩张,并分化为大脑中所有主要细胞类型(即神经元, 神经胶质细胞)。为了开始阐明hcfc1在鼻咽癌扩张中的可能机制,我们创建了Co60等位基因。 这导致了斑马鱼hcfc1a同源基因功能突变的丧失。通过免疫组织化学 标记和细胞计数表明,Co60等位基因(Co60/+)的杂合子携带者增加了 鼻咽癌的扩散。接下来,我们使用Co60/+全脑匀浆的转录组学揭示了14倍的 对细胞增殖和AKT激活至关重要的转录因子ASXL1表达增加 发信号。我们发现,抑制AKT上游激活剂PI3K在Co60/+突变体中恢复了ASXL1 依赖鼻咽癌过度增殖。此外,初步的Western blotting和密度分析我们的 突变体证实AKT(Thr308)过度磷酸化。接下来我们用染色质免疫沉淀来确认 人HCFC1与斑马鱼ASXL1启动子的直接结合。总而言之,这些发现间接地将 首次发现hcfc1a功能和ASXL1表达伴随着AKT的激活和鼻咽癌的增殖。剩下的是什么? 了解的是来自hcfc1a突变体的分离的npC中AKT信号的水平,以及哪个AKT 下游信号分子,如mTOR,调节细胞增殖。完成这项研究将有助于确定 调控脑发育的新分子通路和精确定位机制如下 它的失调如何导致神经发育障碍。在这个奖项的F99阶段,我寻求 获得包括蛋白质分离在内的分子生物学技术的实用知识, 免疫印迹、荧光激活细胞分类(FACS)、流式细胞术、高级成像和行为学 神经科学。此外,我的目标是完善我的技能,并在资质方面获得职业发展, 审稿和准备,建立和维护我的科学网络,完成我的论文 研究。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Victoria L Castro其他文献

Victoria L Castro的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Victoria L Castro', 18)}}的其他基金

Gene regulatory mechanisms governed by the ASXL1/HCF1/OGT complex during neurogenesis
神经发生过程中 ASXL1/HCF1/OGT 复合物控制的基因调控机制
  • 批准号:
    10794902
  • 财政年份:
    2022
  • 资助金额:
    $ 4.14万
  • 项目类别:

相似海外基金

Collaborative Research: Using Adaptive Lessons to Enhance Motivation, Cognitive Engagement, And Achievement Through Equitable Classroom Preparation
协作研究:通过公平的课堂准备,利用适应性课程来增强动机、认知参与和成就
  • 批准号:
    2335802
  • 财政年份:
    2024
  • 资助金额:
    $ 4.14万
  • 项目类别:
    Standard Grant
Collaborative Research: Using Adaptive Lessons to Enhance Motivation, Cognitive Engagement, And Achievement Through Equitable Classroom Preparation
协作研究:通过公平的课堂准备,利用适应性课程来增强动机、认知参与和成就
  • 批准号:
    2335801
  • 财政年份:
    2024
  • 资助金额:
    $ 4.14万
  • 项目类别:
    Standard Grant
A Longitudinal Study of the Relationship between Participation in a Comprehensive Exercise Program and Academic Achievement
参加综合锻炼计划与学业成绩之间关系的纵向研究
  • 批准号:
    24K14615
  • 财政年份:
    2024
  • 资助金额:
    $ 4.14万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Collaborative Research: Characterizing Best Practices of Instructors who Have Narrowed Performance Gaps in Undergraduate Student Achievement in Introductory STEM Courses
合作研究:缩小本科生 STEM 入门课程成绩差距的讲师的最佳实践
  • 批准号:
    2420369
  • 财政年份:
    2024
  • 资助金额:
    $ 4.14万
  • 项目类别:
    Standard Grant
Collaborative Research: Using Adaptive Lessons to Enhance Motivation, Cognitive Engagement, And Achievement Through Equitable Classroom Preparation
协作研究:通过公平的课堂准备,利用适应性课程来增强动机、认知参与和成就
  • 批准号:
    2335800
  • 财政年份:
    2024
  • 资助金额:
    $ 4.14万
  • 项目类别:
    Standard Grant
WTG: Diffusion of Research on Supporting Mathematics Achievement for Youth with Disabilities through Twitter Translational Visual Abstracts
WTG:通过 Twitter 翻译视觉摘要传播支持残疾青少年数学成就的研究
  • 批准号:
    2244734
  • 财政年份:
    2023
  • 资助金额:
    $ 4.14万
  • 项目类别:
    Standard Grant
The Impact of Emotional Experiences of Pride on Long-Term Goal Achievement Behaviors in Elite Athletes
骄傲的情感体验对优秀运动员长期目标实现行为的影响
  • 批准号:
    23K16740
  • 财政年份:
    2023
  • 资助金额:
    $ 4.14万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Meta-Analysis of the Instructional-Relational Model of Student Engagement and Math Achievement: A Moderation and Mediation Approach
学生参与度和数学成绩的教学关系模型的元分析:一种调节和中介方法
  • 批准号:
    2300738
  • 财政年份:
    2023
  • 资助金额:
    $ 4.14万
  • 项目类别:
    Standard Grant
Improving maths achievement in children with speech, language, and communication needs through 'collaborative vocabulary teaching'
通过“协作词汇教学”提高有言语、语言和交流需求的儿童的数学成绩
  • 批准号:
    2890475
  • 财政年份:
    2023
  • 资助金额:
    $ 4.14万
  • 项目类别:
    Studentship
HSI Institutional Transformation Project: Retention and Achievement for Introductory STEM English Learners (RAISE)
HSI 机构转型项目:STEM 英语入门学习者的保留和成就 (RAISE)
  • 批准号:
    2225178
  • 财政年份:
    2023
  • 资助金额:
    $ 4.14万
  • 项目类别:
    Continuing Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了