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干扰而引起的。ARX是同源框转录 已知的调节大脑发育和模式的因子，已被证明导致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，几个突变 已经在这个基因中被鉴定出来，并且突变的类别和由此产生的 表型。初步数据显示，秀丽线虫ALR-1/ARX基因突变导致 GABA能神经元分化、轴突过度伸展和突触形成。因此，中心假设是 不同类别的ALR-1/ARX变异体通过干扰ALR-1/ARX-1的特定子集而导致特定的综合征- 调节基因网络，进而影响神经回路的形成和功能。使用强大的 线虫的遗传学作为模式和发现系统，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和 这一过程的转录调控。此外，导致ARX疾病的突变是如何干扰这些 本课程将探讨神经系统异常连接的过程和结果。 这一发现将确定可能在智力障碍患者中被干扰的新候选基因 残疾人，更重要的是，监管网络负责任。了解他们的颠覆如何导致 有必要进一步阐明导致其他未知ID病例的其他基因 这些可能是ALR-1/ARX的靶点或共同调节因子。这些发现将为 将基础科学成果转化为脊椎动物，最终转移到床边。罗切斯特大学 和它的内分泌科提供了一个独特的协作环境，在基础、临床和 翻译研究，并投资于早期职业科学家的成功。该培训计划充分利用了 申请人雄厚的研究背景和长期感兴趣的神经回路形成结合 波特曼博士的导师。他将接受转录学领域的培训，并掌握尖端技术 在细胞分类、RNA测序和切割和标签测序方面，在该领域的领导者的指导下。 最终，博士后奖学金将允许该研究员扩大他的科学培训，并创造一个 过渡到独立的内科医生-科学家职业生涯所需的独立研究方向。

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