Mutations in HCFC1 alter neural precursor differentiation

项目摘要 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 作为一种模式生物来理解发育障碍的分子基础。我是个终身助理 教授在得克萨斯大学埃尔帕索（UTEP），西班牙裔服务机构，位于美国/墨西哥 边境UTEP致力于解决边境地区新出现的挑战，并制定了 边境生物医学研究中心（BBRC），美国国立卫生研究院差异的一个组成部分 少数民族机构研究中心计划（RCMI），以扩大生物医学研究和加强 区域内的研究基础设施。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。 这个K 01指导职业科学奖的目标是“提供一个研究密集型的指导， 经验，这将最终提高候选人的竞争力水平，为未来的R 01级资金。 为了实现这一目标，我们提出了一个研究密集型培训计划，主要侧重于提高我的 出版记录，并通过利用赞助的计划提供高水平的赠款写作培训， 美国国家研究指导网络（NMRN）和美国细胞生物学学会。我们将补充 这些举措通过提高我的领导技能和我的专业网络。因此，在这结束时， 如果我获得该奖项，我将接受适合我目前职位的专家培训，这将提高我的 R级融资的竞争力。 当前提案的重点是了解与突变相关的潜在机制 在HCFC 1转录辅因子中。HCFC 1的突变导致钴胺素X障碍（cblX），一种多发性骨髓瘤。 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HCFC 1的功能是调节神经前体分化，但这些结果还没有被证实。 在体内证实，因为HCFC 1存在于人类和小鼠的X染色体上， 限制纯合隐性条件性敲除产生的相关补偿机制 小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， 了解HCFC 1的功能。因此，本提案的目标是：1）确定 HCFC 1在体内神经前体特化、增殖和分化中的作用，以及2）确定 HCFC 1通过调节MMAHC基因的表达来调节大脑发育。的结果予以 数据将有助于确定与神经系统疾病相关的新途径和治疗靶点， 神经前体功能的缺陷

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.