Transcriptional regulation of neural circuit formation in intellectual disabilities

智力障碍神经回路形成的转录调控

基本信息

批准号：
10229181
负责人：
Carlos Antonio Diaz-Balzac
金额：
$ 7.05万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-26 至 2024-04-25
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229181
关键词：
Affect Axon Basic Science Binding Biological Markers Brain CRISPR/Cas technology Caenorhabditis elegans Candidate Disease Gene Cell Adhesion Cell Separation Clinical Research Data Defect Development Differentiated Gene Disease Down Syndrome Down Syndrome Cell Adhesion Molecule Endocrinology Etiology Exhibits Extracellular Matrix Failure Fellowship Foundations Functional disorder Future Gene Expression Genes Genetic Genetic Transcription Genomics Genotype Homeobox Human Intellectual functioning disability Investigation Light Link Maintenance Mediating Mentors Modeling Molecular Molecular Genetics Mutate Mutation Nervous system structure Neurologic Deficit Neuronal Differentiation Neurons Neurophysiology - biologic function Neurotransmitters Pathway interactions Patients Pattern Phenotype Physicians Play Process Promoter Regions Public Health Reporter Research Role Scientist Structure Subgroup Synapses Syndrome System Technology Testing Training Transcriptional Regulation Translational Research Translations Universities Variant Vertebrates Work career collaborative environment disease-causing mutation executive function genome editing insight interest mutant nematode genetics neural circuit neurodevelopment neurogenetics neuronal circuitry novel success synaptogenesis therapeutic development transcription factor transcriptome transcriptome sequencing transcriptomics

项目摘要

Project Summary Intellectual disabilities arise from disruption of normal brain function. ARX is a homeobox transcription factor known to regulate brain development and patterning, which has been shown to cause an X-linked form of intellectual disability and other syndromes associated with neurological deficits. Moreover, several mutations have been identified in this gene, and there is a correlation between the class of mutation and the resulting phenotype. Preliminary data shows that mutations in alr-1/ARX in Caenorhabditis elegans result in defects in GABAergic neuronal differentiation, axon overextension, and synaptogenesis. Thus, the central hypothesis is that different classes of alr-1/ARX variants cause specific syndromes by disrupting specific subsets of alr-1/ARX- regulated gene networks, which in turn affects the formation and function of neural circuits. Using the powerful genetics of the nematode C. elegans as a model and discovery system, alr-1/ARX cellular and molecular function will be dissected to gain mechanistic insight into the role of alr-1/ARX in neural circuit formation and the transcriptional regulation of this process. Additionally, how ARX disease-causing mutations disturb these processes and results in abnormal wiring of the nervous system will be explored. The findings will identify novel candidate genes that may be disrupted in patients with intellectual disabilities and more importantly, the regulatory network responsible. Understanding how their disruption leads to the phenotype is necessary to further elucidate other genes responsible for other unknown cases of ID given that these are likely targets or co-regulators of alr-1/ARX. These findings will establish the ground for the translation of the basic science results to vertebrates and eventually to the bedside. The University of Rochester and its Endocrinology division provide a unique collaborative environment of excellence in basic, clinical and translational research, and is invested in the success of early career scientists. The training plan capitalizes on the applicant’s strong research background and long-standing interest neural circuit formation combined with the mentoring of Dr. Portman. He will obtain training in the transcriptomics field, and master cutting-edge technology in cell-sorting, RNA-sequencing and Cut&Tag-sequencing, while being mentored by leaders in the field. Ultimately, the postdoctoral fellowship will allow the fellow to expand his scientific training and create an independent line of investigation needed for transitioning to an independent physician-scientist career.

项目概要 ARX 是一种同源盒转录，导致智力障碍。已知调节大脑发育和模式的因子，已被证明会导致 X 连锁形式的此外，还有一些与神经缺陷相关的智力障碍和其他综合症。已在该基因中鉴定出突变类别与所得结果之间存在相关性初步数据显示，秀丽隐杆线虫中的 alr-1/ARX 突变会导致缺陷。 GABA能神经元分化、轴突过度延伸和突触发生因此，中心假设是。不同类别的 alr-1/ARX 变异体通过破坏 alr-1/ARX 的特定子集而引起特定的综合征调节基因网络，进而影响神经回路的形成和功能。线虫遗传学作为模型和发现系统，alr-1/ARX 细胞和分子功能将进行剖析，以深入了解 alr-1/ARX 在神经回路形成中的作用以及此外，ARX 致病突变如何干扰这些过程。将探讨神经系统异常连接的过程和结果。研究结果将鉴定出可能在智力障碍患者中被破坏的新候选基因。残疾，更重要的是，了解他们的破坏如何导致。为了进一步阐明导致其他未知 ID 病例的其他基因，有必要对表型进行研究这些发现可能是 alr-1/ARX 的目标或共同调节者。将基础科学成果转化为脊椎动物并最终转化为罗切斯特大学的临床成果。及其内分泌科在基础、临床和内分泌方面提供了一个独特的卓越协作环境转化研究，并投资于早期职业科学家的成功。申请人深厚的研究背景和长期以来对神经回路形成的兴趣结合他将在Portman博士的指导下获得转录组学领域的培训，并掌握尖端技术。在细胞分选、RNA 测序和切割和标签测序方面拥有丰富的经验，同时受到该领域领导者的指导。最终，博士后奖学金将使该研究员能够扩大他的科学培训并创造一个过渡到独立的医师科学家职业所需的独立调查线。