Regulatory mechanisms of cerebellar lineage development
小脑谱系发育的调节机制
基本信息
- 批准号:10799998
- 负责人:
- 金额:$ 55.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-15 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAtaxiaBindingBinding SitesBrainCDK4 geneCell CycleCell Cycle ProgressionCell LineageCerebellar DiseasesCerebellumClustered Regularly Interspaced Short Palindromic RepeatsComplexCongenital cerebellar hypoplasiaDataDevelopmentDiseaseDown-RegulationEmbryoEnhancersEpigenetic ProcessFeedbackFoundationsGene ExpressionGenerationsGenesGenetic TranscriptionGoalsHistone DeacetylaseHumanKnowledgeLearningModelingMotorNeuronsNucleic Acid Regulatory SequencesOutcomePlayPost-Translational RegulationPremature InfantProliferatingProteinsRepressionRisk FactorsRoleSignal TransductionSystemTestingTimeTranscription RepressorZinc Fingersautism spectrum disordercell typecognitive taskgenetic corepressorgranule cellinsulinoma associated 1medulloblastomamotor behaviornervous system disordernovelpostmitoticpostnatalprotein degradationsensory integrationtranscription factor
项目摘要
PROJECT SUMMARY
Granule cells (GCs) constitute over 95% of the cerebellar volume. They receive and integrate sensory, motor,
and non-sensorimotor signals to fine-tune motor behaviors and cognitive tasks. GCs are generated from
transiently proliferating granule cell precursors (GCPs) over a long time extending from early embryonic period
until first postnatal year in human. Accordingly, cerebellar hypoplasia is one of the most common brain
complications in premature infants with poor developmental outcomes. We have very limited basic knowledge
of how GC lineage is established. Our long term goals are to elucidate the regulatory mechanisms of GC lineage
development, and to understand how different risk factors cause cerebellar hypoplasia. A master regulator of
GCP development is the bHLH transcription factor Atoh1 that maintains the GCP fate through activation of its
own expression. This autoregulatory feedback loop is further supported by a cell cycle regulator Ccnd1 that
stabilizes Atoh1 protein from degradation. However, it remains unclear as to how Atoh1 and Ccnd1 expressions
are terminated to enable timely progression from GCPs to GCs. Our preliminary data suggest that Sin3A, a
component of histone deacetylase (Hdac)–containing transcriptional corepressor complex, is essential for GCP
differentiation by epigenetically silencing Atoh1 expression. We have also identified Insm1, a zinc-finger
transcription factor, as a potential partner of the Sin3A-Hdac complex that inhibits Atoh1 and Ccnd1 expression.
Based on these and other preliminary observations, we propose the novel hypothesis that Atoh1 expression is
dynamically controlled by H3K27 epigenetic signatures at the Atoh1 enhancer, with Insm1 as a key
transcriptional repressor disrupting the Atoh1 autoregulatory loop and cell cycle progression, and enabling GC
lineage differentiation. This hypothesis will be tested by determining (1) the epigenetic mechanism of Atoh1
expression and GC lineage differentiation, (2) Insm1 function and regulatory landscape during GC lineage
development, and (3) the contribution of Insm1 in Atoh1 protein stability and GC lineage progression.
项目摘要
颗粒细胞(GC)占小脑体积的95%以上。他们接收并整合感觉,运动,
和非感觉运动信号来微调运动行为和认知任务。GC生成自
从胚胎早期开始的很长一段时间内短暂增殖的颗粒细胞前体(GCP)
直到人类出生后的第一年。因此,小脑发育不全是最常见的脑
早产儿并发症与不良的发展结果。我们的基本知识非常有限
GC血统是如何建立的我们的长期目标是阐明GC谱系的调控机制
发展,并了解不同的风险因素如何导致小脑发育不全。的主要调节剂
GCP的形成是bHLH转录因子Atoh 1,它通过激活
自己的表达。这种自动调节反馈循环进一步得到细胞周期调节因子Ccnd 1的支持,
稳定Atoh 1蛋白质免于降解。然而,Atoh 1和Ccnd 1的表达如何影响细胞的功能仍不清楚。
终止,以便及时从GCP进展到GC。我们的初步数据表明,Sin 3A,
组蛋白去乙酰化酶(HSP 70)的转录辅抑制因子复合物的组成部分,是GCP所必需的
通过表观遗传学沉默Atoh 1表达来分化。我们还鉴定了一种锌指蛋白Insm 1,
转录因子,作为抑制Atoh 1和Ccnd 1表达的Sin 3A-Hind复合物的潜在伴侣。
基于这些和其他初步观察,我们提出了新的假设,Atoh 1表达是
由Atoh 1增强子处的H3 K27表观遗传特征动态控制,Insm 1是关键
转录抑制因子破坏Atoh 1自动调节环和细胞周期进程,
谱系分化这一假设将通过确定(1)Atoh 1的表观遗传机制来检验
(2)Insm 1在胃癌细胞分化过程中的功能和调控格局
(3)Insm 1在Atoh 1蛋白稳定性和GC谱系进展中的作用。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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CHIN CHIANG其他文献
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{{ truncateString('CHIN CHIANG', 18)}}的其他基金
Regulation of Shh Signaling by Cellular Energetics
细胞能量学对 Shh 信号传导的调节
- 批准号:
9356584 - 财政年份:2016
- 资助金额:
$ 55.48万 - 项目类别:
Regulation of Shh Signaling by Cellular Energetics
细胞能量学对 Shh 信号传导的调节
- 批准号:
10001606 - 财政年份:2016
- 资助金额:
$ 55.48万 - 项目类别:
Regulation of Shh Signaling by Cellular Energetics
细胞能量学对 Shh 信号传导的调节
- 批准号:
9235988 - 财政年份:2016
- 资助金额:
$ 55.48万 - 项目类别:
Regulation of Shh Signaling by Cellular Energetics
细胞能量学对 Shh 信号传导的调节
- 批准号:
9768250 - 财政年份:2016
- 资助金额:
$ 55.48万 - 项目类别:
Regulation of Shh Signaling Activity in Limb Patterning
肢体模式中 Shh 信号活动的调节
- 批准号:
7267724 - 财政年份:2006
- 资助金额:
$ 55.48万 - 项目类别:
Regulation of Shh Signaling Activity in Limb Patterning
肢体模式中 Shh 信号活动的调节
- 批准号:
7630604 - 财政年份:2006
- 资助金额:
$ 55.48万 - 项目类别:
Regulation of Shh Signaling Activity in Limb Patterning
肢体模式中 Shh 信号活动的调节
- 批准号:
7145045 - 财政年份:2006
- 资助金额:
$ 55.48万 - 项目类别:
Regulation of Shh Signaling Activity in Limb Patterning
肢体模式中 Shh 信号活动的调节
- 批准号:
7846200 - 财政年份:2006
- 资助金额:
$ 55.48万 - 项目类别:
Regulation of Shh Signaling Activity in Limb Patterning
肢体模式中 Shh 信号活动的调节
- 批准号:
7439149 - 财政年份:2006
- 资助金额:
$ 55.48万 - 项目类别:
Control of Shh Activity and Signaling in the Neural Tube
神经管中 Shh 活动和信号传导的控制
- 批准号:
8140658 - 财政年份:2001
- 资助金额:
$ 55.48万 - 项目类别:
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