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Mutations in HCFC1 alter neural precursor differentiation

HCFC1 突变改变神经前体分化

基本信息

批准号：
9768561
负责人：
Anita M Quintana
金额：
$ 23.31万
依托单位：
UNIVERSITY OF TEXAS EL PASO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9768561
关键词：
Address Affect Alleles American Amino Acids Animal Model Award Biological Models Biomedical Research Birth Brain CRISPR/Cas technology Cellular biology Clinical Cobalamin Complement Craniofacial Abnormalities DNA Binding Data Defect Development Disease Educational Status Embryo Exhibits Fishes Fourth ventricle structure Funding Future Gene Expression Generations Genes Genetic Transcription Germ-Line Mutation Goals Grant Hispanic-serving Institution Human Immunohistochemistry Impairment In Situ Hybridization In Vitro Intellectual functioning disability Intractable Epilepsy Knockout Mice Leadership Link Maintenance Mediating Mentors Messenger RNA Metabolism Mexican Midbrain structure Minority-Serving Institution Missense Mutation Molecular Mus Mutation Neurodevelopmental Deficit Neurologic Neurologic Deficit Neurologic Symptoms Orthologous Gene Pathway interactions Patients Phenotype Physiological Positioning Attribute Production Proteins Publications Research Research Infrastructure Role Science Sex Chromosomes Single-Gene Defect Societies Syndrome System Tegmentum Mesencephali Testing Texas Time Tissues Training Transgenes United States National Institutes of Health Universities Work World Health Organization Writing X Chromosome Zebrafish base career career networking clinically relevant cofactor congenital anomaly developmental disease experience experimental study genome editing health disparity host cell factor C1 improved in vivo in vivo Model knock-down mutant nerve stem cell nervous system disorder novel professor programs skills tenure track therapeutic target transcription factor

项目摘要

Project Summary My overarching scientific goal is to develop a cross disciplinary research program that utilizes zebrafish as a model organism to understand the molecular basis of developmental disorders. I am a tenure track assistant professor at The University of Texas El Paso (UTEP), a Hispanic serving institution, located on the US/Mexican border. UTEP is dedicated to addressing the emerging challenges of the border region and has developed the Border Biomedical Research Center (BBRC), a component of the National Institutes of Health Disparities Research Centers in Minority Institutions Program (RCMI) to expand biomedical research and strengthen the research infrastructure within the region. My research complements the goals of both UTEP and the BBRC, thus I am perfectly positioned to develop a successful cross disciplinary research program. The goal of this K01 mentored career science award is “to provide a research intensive mentored experience, which will ultimately increase the candidate’s level of competitiveness for future R01 level funding.” To meet this goal, we propose a research intensive training plan, which focuses primarily on improving my publication record and providing high level training in grant writing by utilizing programs sponsored by the National Research Mentoring Network (NMRN) and the American Society for Cell Biology. We will complement these initiatives by enhancing my leadership skills and my professional network. Therefore, at the end of this award, I will have received expert training appropriate to my current position, which will improve my competitiveness for R-level funding. The focus of the current proposal is understand the underlying mechanisms associated with mutations in the HCFC1 transcriptional cofactor. Mutations in HCFC1 cause cobalamin X disorder (cblX), a multiple congenital anomaly syndrome associated with severe neurological and neurodevelopmental deficits. In vitro studies suggest HCFC1 functions to modulate neural precursor differentiation, but these results have not been confirmed in vivo because HCFC1 is present on the X-chromosome in humans and mice and is subject to X- linked compensatory mechanisms which limit the production of homozygous recessive conditional knockout mice. Zebrafish do not have sex chromosomes and therefore represent a unique and powerful system in which to understand the function of in HCFC1. Therefore, the goals of this proposal are 1) to determine the function of HCFC1 in neural precursor specification, proliferation, and differentiation in vivo and 2) to determine whether HCFC1 regulates brain development by modulating the expression of the MMACHC gene. The results of these data will help to identify novel pathways and therapeutic targets for neurological disorders associated with defects in neural precursor function.

项目概要我的首要科学目标是开发一个利用斑马鱼的跨学科研究项目作为模型生物体来了解发育障碍的分子基础。我是终身教职助理德克萨斯大学埃尔帕索分校 (UTEP) 教授，一所位于美国/墨西哥的西班牙裔服务机构边界。 UTEP 致力于解决边境地区新出现的挑战，并开发了边境生物医学研究中心 (BBRC)，隶属于美国国立健康差距研究所少数民族机构研究中心计划（RCMI）旨在扩大生物医学研究并加强该地区的研究基础设施。我的研究补充了 UTEP 和 BBRC 的目标，因此我完全有能力开发一个成功的跨学科研究项目。 K01 指导型职业科学奖的目标是“提供研究密集型指导型职业科学奖” 经验，这最终将提高候选人未来 R01 级资助的竞争力水平。” 为了实现这一目标，我们提出了一项研究强化培训计划，该计划主要侧重于提高我的能力出版记录并利用资助项目提供高水平的资助写作培训国家研究指导网络 (NMRN) 和美国细胞生物学学会。我们将补充这些举措通过增强我的领导技能和我的专业网络来实现。因此，在本期结束时获奖后，我将接受适合我当前职位的专家培训，这将提高我的能力 R 级资金的竞争力。当前提案的重点是了解与突变相关的潜在机制 HCFC1 转录辅助因子中。 HCFC1 突变会导致钴胺素 X 紊乱 (cblX)，这是一种多发性疾病与严重神经和神经发育缺陷相关的先天性异常综合征。体外研究表明 HCFC1 具有调节神经前体分化的功能，但这些结果尚未得到证实在体内得到证实，因为 HCFC1 存在于人类和小鼠的 X 染色体上，并且受到 X- 限制纯合隐性条件敲除产生的连锁补偿机制老鼠。斑马鱼没有性染色体，因此代表了一个独特而强大的系统，其中了解HCFC1中的功能。因此，本提案的目标是 1) 确定 HCFC1 在体内神经前体规范、增殖和分化中的作用，以及 2) 确定是否 HCFC1 通过调节 MMACHC 基因的表达来调节大脑发育。这些结果数据将有助于确定与相关神经系统疾病的新途径和治疗靶点神经前体功能缺陷。