Transcriptional regulation of neural circuit formation in intellectual disabilities

智力障碍神经回路形成的转录调控

• 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
• 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

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 智力残疾是由于正常的大脑功能受到破坏而产生的。ARX是一种同源框转录 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 智力残疾和其他与神经缺陷相关的综合征。此外，一些突变 已经在这个基因中被鉴定出来，并且突变的类型和所产生的结果之间存在相关性。 表型初步数据显示，秀丽隐杆线虫中alr-1/ARX的突变导致了 γ-氨基丁酸能神经元分化、轴突过度伸展和突触发生。因此，中心假设是 不同种类的alr-1/ARX变体通过破坏alr-1/ARX的特定子集而引起特定综合征， 调节基因网络，这反过来又影响神经回路的形成和功能。使用强大的 线虫C. elegans作为模型和发现系统，alr-1/ARX细胞和分子功能 将被解剖，以获得对alr-1/ARX在神经回路形成中的作用的机制性见解， 该过程的转录调节。此外，ARX致病突变如何干扰这些 神经系统的异常布线的过程和结果将被探索。 这些发现将确定可能在智力低下患者中被破坏的新的候选基因。 残疾人，更重要的是，监管网络负责。了解他们的破坏如何导致 对表型的研究对于进一步阐明其他未知ID病例的其他基因是必要的。 这些可能是alr-1/ARX的靶点或协同调节因子。这些发现将为 将基础科学成果转化为脊椎动物，并最终应用于临床。罗切斯特大学 及其内分泌科提供了一个独特的协作环境，在基础，临床和 转化研究，并投资于早期职业科学家的成功。培训计划利用 申请人强大的研究背景和长期的兴趣神经回路形成结合， 波特曼博士的指导他将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，同时在该领域的领导者指导。 最终，博士后奖学金将使研究员扩大他的科学训练，并创造一个 独立的调查路线需要过渡到一个独立的医生，科学家的职业生涯。

项目成果

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