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:
- 金额:$ 7.05万
- 依托单位:
- 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:
- 关键词:AffectAxonBasic ScienceBindingBiological MarkersBrainCRISPR/Cas technologyCaenorhabditis elegansCandidate Disease GeneCell AdhesionCell SeparationClinical ResearchDataDefectDevelopmentDifferentiated GeneDiseaseDown SyndromeDown Syndrome Cell Adhesion MoleculeEndocrinologyEtiologyExhibitsExtracellular MatrixFailureFellowshipFoundationsFunctional disorderFutureGene ExpressionGenesGeneticGenetic TranscriptionGenomicsGenotypeHomeoboxHumanIntellectual functioning disabilityInvestigationLightLinkMaintenanceMediatingMentorsModelingMolecularMolecular GeneticsMutateMutationNervous system structureNeurologic DeficitNeuronal DifferentiationNeuronsNeurophysiology - biologic functionNeurotransmittersPathway interactionsPatientsPatternPhenotypePhysiciansPlayProcessPromoter RegionsPublic HealthReporterResearchRoleScientistStructureSubgroupSynapsesSyndromeSystemTechnologyTestingTrainingTranscriptional RegulationTranslational ResearchTranslationsUniversitiesVariantVertebratesWorkcareercollaborative environmentdisease-causing mutationexecutive functiongenome editinginsightinterestmutantnematode geneticsneural circuitneurodevelopmentneurogeneticsneuronal circuitrynovelsuccesssynaptogenesistherapeutic developmenttranscription factortranscriptometranscriptome sequencingtranscriptomics
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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Carlos Antonio Diaz-Balzac其他文献
Carlos Antonio Diaz-Balzac的其他文献
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{{ truncateString('Carlos Antonio Diaz-Balzac', 18)}}的其他基金
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:
10433857 - 财政年份:2021
- 资助金额:
$ 7.05万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 7.05万 - 项目类别:
Identification of Novel Loci Interacting with the Kallmann Syndrome Gene Kal-1
与卡尔曼综合征基因 Kal-1 相互作用的新位点的鉴定
- 批准号:
8513379 - 财政年份:2010
- 资助金额:
$ 7.05万 - 项目类别:
Identification of Novel Loci Interacting with the Kallmann Syndrome Gene Kal-1
与卡尔曼综合征基因 Kal-1 相互作用的新位点的鉴定
- 批准号:
8244420 - 财政年份:2010
- 资助金额:
$ 7.05万 - 项目类别:
Identification of Novel Loci Interacting with the Kallmann Syndrome Gene Kal-1
与卡尔曼综合征基因 Kal-1 相互作用的新位点的鉴定
- 批准号:
8006683 - 财政年份:2010
- 资助金额:
$ 7.05万 - 项目类别:
Identification of Novel Loci Interacting with the Kallmann Syndrome Gene Kal-1
与卡尔曼综合征基因 Kal-1 相互作用的新位点的鉴定
- 批准号:
8309394 - 财政年份:2010
- 资助金额:
$ 7.05万 - 项目类别:
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