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.

项目摘要智力障碍是由于正常脑功能的破坏而引起的。 ARX是同型转录已知可以调节大脑发育和图案的因素，这已被证明引起X连锁形式的与神经系统缺陷相关的智力残疾和其他综合症。而且，几个突变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。初步数据表明，秀丽隐杆线虫中ALR-1/ARX突变导致缺陷 GABA能神经元分化，轴突过度延伸和突触发生。那是中心假设不同类别的ALR-1/ARX变体通过破坏ALR-1/ARX-的特定子集引起特定综合征调节的基因网络反过来影响神经回路的形成和功能。使用强大的线虫C.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在神经回路形成和该过程的转录调节。此外，如何引起ARX致病突变干扰这些将探索神经系统异常接线的过程和结果。这些发现将确定智力患者可能中断的新型候选基因残疾，更重要的是，监管网络负责。了解他们的破坏如何导致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的目标或共同调节剂。这些发现将为将基础科学的翻译结果转换为脊椎动物，并最终向床边。罗切斯特大学它的内分泌学部提供了一个独特的基础，临床和卓越协作环境翻译研究，并投资于早期职业科学家的成功。培训计划大写申请人的强大研究背景和长期有趣的神经元电路形成结合 Portman博士的指导。他将获得转录组学领域的培训，并获得尖端技术在细胞分类，RNA测序和剪切和标签测序中，同时被现场的领导者考虑。最终，博士后奖学金将使该研究员扩大他的科学培训并创建一个过渡到独立的身体科学家职业所需的独立调查线。

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