Role of TRIM71 in neural stem cell biology and congenital hydrocephalus
TRIM71 在神经干细胞生物学和先天性脑积水中的作用
基本信息
- 批准号:10313612
- 负责人:
- 金额:$ 3.09万
- 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:2021-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:Academic skillsAffectAnimalsBiologicalBiological ProcessBiologyBirthBrainBrain DiseasesCaenorhabditis elegansCell Culture TechniquesCell physiologyCellsCerebral VentriclesCerebrospinal FluidCerebrospinal fluid shunts procedureChildhoodClinicalColony-Forming Units AssayCommunicating HydrocephalusComplementCongenital HydrocephalusCoupledDefectDevelopmentDevelopmental Brain MalformationDiagnosticEducational workshopExhibitsFailureFluid BalanceFluids and SecretionsFunctional disorderFutureGenesGeneticGoalsHistologyHomologous GeneHumanHydrocephalusImpairmentIn VitroIntracranial PressureKnowledgeLaboratoriesLeadLearningLive BirthMagnetic Resonance ImagingMeasurementMeasuresMedicineMicroRNAsModelingMolecularMolecular GeneticsMorbidity - disease rateMorphogenesisMusMutant Strains MiceMutateMutationNatureNeonatalNeuroanatomyNeurodevelopmental DisorderNeuroepithelial CellsNeurosciencesNeurosurgeonOperative Surgical ProceduresOutcomePathogenesisPathway interactionsPatientsPhylogenyPhysiciansPhysiologicalPhysiologyPreventive measureRNA-Binding ProteinsRegulationResearchRoleSchemeScientistSeriesStem cell pluripotencyTechniquesTestingTherapeuticTrainingWorkabsorptionbasecareercerebrospinal fluid flowclinical decision-makingde novo mutationepidermal stem cellexome sequencinghistological studiesimprovedin vitro Assayinsightmortalitymouse modelmultidisciplinarymutantmutant mouse modelneocorticalnerve stem cellnestin proteinneurogenesisneurogenomicsneuroimagingnovelnovel markerpre-clinicalprecision medicineprenatalprognosticstem cell biologystem cell differentiationstem cell populationstem cell proliferationtargeted treatmenttranscriptomeventricular system
项目摘要
PROJECT SUMMARY
Congenital hydrocephalus (CH) is the most common developmental malformation of the brain affecting
1/1000 births. CH has been classically attributed to failed cerebrospinal fluid (CSF) homeostasis and
therefore treated by surgical CSF diversion, with high morbidity and failure rates. The persistence of post-
surgical ventriculomegaly in many patients, often with poor neurodevelopmental outcomes, raises questions
about our current paradigms of CH and its treatment. Significant gaps in our understanding of the molecular
pathogenesis of CH impede the development of preventive measures, targeted therapies, and improved
prognostication. By whole exome sequencing, the Kahle lab has identified heterozygous de novo
mutations in the TRIM71/lin-41 as the most common genetic cause of human sporadic CH (Jin et al.
2020, Nature Medicine). TRIM71 encodes an RNA-binding protein first discovered in C. elegans as a
heterochronic gene that regulates developmental timing of epidermal stem cells. Despite its remarkable
evolutionary conservation across phylogeny and robust expression in prenatal neural stem cells (NSCs), the
roles of TRIM71 in mammalian brain development and CH are essentially unknown. In preliminary work, I
have shown that mouse lines with the murine homolog of the human TRIM71 CH mutation R608H
(Trim71R595H/+) or with conditional NSC-specific Trim71 deletion (Nestin-Trim71fl/fl) both recapitulate
the severe neonatal-onset communicating hydrocephalus of human patients harboring TRIM71
mutations. The objective of my proposal is to further characterize these models to increase knowledge of
human brain development and CH pathogenesis. I hypothesize TRIM71 mutant ventriculomegaly results not
from primary cerebrospinal fluid (CSF) over-accumulation, but rather from impaired neurogenesis related to
reduced NSC proliferation and precocious NSC differentiation. Aim 1 will characterize the neuroanatomy and
CSF physiology of TRIM71-mutant hydrocephalus using brain magnetic resonance imaging (MRI) and direct
measurements of CSF hydrodynamics. Aim 2 will elucidate the cellular mechanisms of TRIM71-mutant
hydrocephalus using immunofluorescent studies in Trim71 CH mutant mice complemented by in vitro assays
using primary NSC cultures. The demonstration that dysregulated neurogenesis rather than primary CSF
over-accumulation underlies some CH cases could have paradigm-changing implications that could lead to
improved diagnostic, prognostic, and therapeutic strategies, including the prediction of which CH patients
may or may not benefit from neurosurgical CSF shunting. These studies will be conducted as part of our
long-term goal to develop precision medicine therapies for CH.
项目总结
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Duy Phan其他文献
Duy Phan的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Duy Phan', 18)}}的其他基金
Role of TRIM71 in neural stem cell biology and congenital hydrocephalus
TRIM71 在神经干细胞生物学和先天性脑积水中的作用
- 批准号:
10470129 - 财政年份:2021
- 资助金额:
$ 3.09万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 3.09万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 3.09万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 3.09万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 3.09万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 3.09万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 3.09万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 3.09万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 3.09万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 3.09万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 3.09万 - 项目类别:
Studentship