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：
10612463
负责人：
Carlos Antonio Diaz-Balzac
金额：
$ 2.32万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10612463
关键词：
Affect Axon Basic Science Binding Biological Markers Brain CRISPR/Cas technology Caenorhabditis elegans Candidate Disease Gene Cell Adhesion Cell Separation Classification 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 Investments Link Maintenance Mediating Mentors Modeling Molecular Mutate Mutation Nervous System Neurologic Deficit Neuronal Differentiation Neurons Neurophysiology - biologic function Neurotransmitters Pathway interactions Patients Pattern Phenotype Physicians Play Postdoctoral Fellow 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 candidate identification career collaborative environment disease-causing mutation executive function gene network genome editing insight interest mutant nematode genetics neural circuit neurodevelopment neurogenetics neuronal circuitry novel success synaptogenesis therapeutic development transcription factor transcription regulatory network transcriptome sequencing transcriptomic profiling transcriptomics translational pipeline

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.

项目摘要智力上的迹象是由正常脑功能的破坏引起的。已知的因素是常规的大脑发育和图案，这是导致X连锁形式的智力上的抑制性和与神经缺陷相关的其他综合症。已经在该基因中鉴定出来，突变类别与结果之间存在相关性表型。 GABA能神经元分化，轴突过伸展和突触发生。不同类别的ALR-1/ARX变体Cauiants通过破坏ALR-1/ARX-的特定子集引起综合征常规基因网络，进而影响神经回路的形成和功能。线虫秀丽隐杆线虫作为模型和发现系统的遗传学，ALR-1/ARX细胞和分子功能将解剖以获取机械洞察Alr-1/arx inrx inrx inrx inrx inrx在神经回路形成和此过程的转录调节。将探索神经系统异常接线的过程和结果。这些发现将候选候选基因，这些基因受到智力患者的破坏不像是规律性网络响应，更重要的是。表型对于进一步阐明其他未知病例的其他基因是必要的这些可能是ALR-1/ARX的靶标或共同体。将基础科学的结果翻译成脊椎动物，最终向床边翻译。和分泌部提供了独特的基础，临床和卓越卓越协作环境转化研究，并赋予早期职业科学家的成功。申请人的强大研究背景和长期的兴趣神经回路形成与之结合 Portman博士的指导。在细胞分类，RNA测序和剪切和标签测序中，同时受到现场领导者的指导。最终，博士后奖学金将把他的科学培训扩展并创建一个过渡到独立的凹痕医师科学家职业所需的独立调查。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons.

DOI：
10.7554/elife.85792
发表时间：
2023-06-20
期刊：
eLife
影响因子：
7.7
作者：
Lazaro-Pena MI;Cornwell AB;Diaz-Balzac CA;Das R;Ward ZC;Macoretta N;Thakar J;Samuelson AV
通讯作者：
Samuelson AV