Developmental Origin, Injury and Epigenomic Regulation of NF1-Associated Peripheral Nerve Sheath Tumors
NF1相关周围神经鞘肿瘤的发育起源、损伤和表观基因组调控
基本信息
- 批准号:10219631
- 负责人:
- 金额:$ 72.33万
- 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:2021-04-15 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AxonBenignCDKN2A geneCause of DeathCell LineageCharacteristicsChromatinComplexDataDefectDevelopmentEnvironmentFoundationsGene ExpressionGeneticGenomeGrowthHumanIndividualInduced MutationInjuryIntegrinsLesionMEKsMalignant - descriptorMediatingMolecularMusMutant Strains MiceMutationNF1 geneNerveNeural CrestNeurodevelopmental DisorderNeurofibromatosis 1NeurofibrosarcomaOncogenicPatientsPeripheral Nerve Sheath NeoplasmPeripheral NervesPlexiform NeurofibromaPolycombPre-Clinical ModelPreventiveRegulationRiskRoleSchwann CellsSolidTP53 geneTechnologyTestingTherapeuticTreatment ProtocolsTumor Suppressor GenesTumor Suppressor Proteinsaxonal degenerationbasederepressiondrug repurposingeffective therapyembryonic stem cellepigenomicsgenetic signaturehistone modificationin vitro Assayin vivoinjuredmultiple omicsmyelinationneoplastic cellnerve injurynovel therapeutic interventionnovel therapeuticspreventresponse to injurystem cell differentiationstem-like celltranscriptomicstumor
项目摘要
Project Abstract
Individuals with neurofibromatosis type 1 (NF1) have an approximately 160-fold increased risk of developing
malignant peripheral nerve sheath tumor (MPNST). As a leading cause of death for NF1 patients. MPNST
has no effective therapy and thus there is an urgent need for new therapies. The dramatically increased risk of
developing MPNSTs is caused by the presence of plexiform neurofibromas (PNFs), the major benign precursor
lesion for NF1-MPNST. It has been proposed that PNFs are congenital lesions, arising from the early stages of
nerve development when neural-crest stem cells differentiate into Schwann cell (SC) lineages, which give rise
to either myelinating or nonmyelinating SCs (mSCs or nmSCs). In the normal nerve, unmyelinated axons are
sorted and ensheathed by nmSCs into individual pockets, forming Remak bundles. Whereas no defect in SC
precursors or mSCs was observed, Nf1 loss (Nf1-/-) during early nerve development induced a pocket defect in
Remak bundles, characterized by abnormally sorted unmyelinated axons. These abnormal Remak pockets
progress to a stage with axonal degeneration and abnormal proliferation of dissociated SCs, leading to the
formation of PNFs. Axonal degeneration may contribute to PNF formation by inducing a nerve injury
environment, a concept supported by the observation that Nf1 loss in mature SCs is not sufficient to induce
PNFs unless an injury to the nerve occurs. Malignant transformation of PNFs to MPNSTs requires at least two
additional genetic alterations: sequential inactivation of CDKN2A, and then either SUZ12 or EED - two
essential components of Polycomb Repressive Complex 2 (PRC2). PRC2 catalyzes histone modification
H3K27me3 to repress gene expression throughout the genome. Loss of PRC2 specifically observed in
MPNSTs, but not in benign tumors, suggests that PRC2-mediated H3K27me3 normally represses expression
of the oncogenic drivers responsible for malignant transformation of PNFs to MPNSTs. However, Eed/PRC2 is
dispensable during normal mouse SC development and myelination. Further, loss of the Eed/PRC2 tumor
suppressor unexpectedly inhibits proliferation of injury-induced reprogrammed SCs, accompanied by
derepression of Cdkn2a expression. Here, we propose to test two related hypotheses: (1) the developmental
Nf1-/- Remak pocket defect and its associated axonal degeneration (nerve injury) drive Nf1-/- SCs to form PNFs
and (2) nerve injury response induces an epigenomic switch, rendering reprogrammed PNFs or SCs
susceptible to malignant transformation by sequential loss of CDKN2A and PRC2. We will determine the role
of the developmental Remak pocket defect in NF1-MPNST formation (Aim 1), investigate tumor suppressive
mechanisms in injury-induced reprogramed SCs (Aim 2), and develop therapeutic strategies based on the
injury-induced epigenomic switch in reprogrammed SCs (Aim 3). We will identify injury-induced and PRC2-
repressed oncogenic drivers for MPNST formation via epigenomic approaches, develop synergistic therapies
using a high-throughput drug repurposing screen, and test them GEM- and patient-derived preclinical models.
项目摘要
患有1型神经纤维瘤病(NF 1)的个体发生以下疾病的风险增加约160倍:
恶性周围神经鞘瘤(MPNST)。是NF 1患者死亡的主要原因。MPNST
没有有效的疗法,因此迫切需要新的疗法。急剧增加的风险,
发展中的MPNST是由丛状神经纤维瘤(PNF)的存在引起的,PNF是主要的良性前体
NF 1-MPNST病变。已经提出PNF是先天性病变,由PNF的早期阶段引起。
当神经嵴干细胞分化成雪旺细胞(SC)谱系时,
髓鞘形成或非髓鞘形成SC(mSC或nmSC)。在正常神经中,无髓鞘轴突
被nmSC分选并包被到单独的口袋中,形成Remak束。而SC中没有缺陷
前体细胞或mSCs,在早期神经发育过程中Nf 1丢失(Nf 1-/-)诱导了一个口袋缺陷,
Remak束,以异常排列的无髓鞘轴突为特征。这些不正常的雷马克口袋
发展到轴突变性和分离的SC异常增殖的阶段,导致
PNF的形成。轴突变性可能通过诱导神经损伤而促进PNF的形成
环境,这一概念得到以下观察结果的支持:成熟SC中的Nf 1损失不足以诱导
PNF,除非发生神经损伤。PNF向MPNST的恶性转化需要至少两个
额外的遗传改变:CDKN 2A的顺序失活,然后SUZ 12或EED -两个
Polycomb Repressive Complex 2(PRC 2)的主要成分。PRC 2催化组蛋白修饰
H3 K27 me 3抑制整个基因组的基因表达。PRC 2的丢失在以下中特别观察到:
MPNSTs,而不是在良性肿瘤中,表明PRC 2介导的H3 K27 me 3通常抑制表达
PNF向MPNST恶性转化的致癌驱动因素。然而,Eed/PRC 2
在正常小鼠SC发育和髓鞘形成过程中,此外,Eed/PRC 2肿瘤的丢失
抑制剂意外地抑制损伤诱导的重编程SC的增殖,伴随着
Cdkn 2a表达的去阻遏。在这里,我们提出了两个相关的假设:(1)发展的
Nf 1-/- Remak口袋缺陷及其相关的轴突变性(神经损伤)驱动Nf 1-/-SC形成PNF
和(2)神经损伤反应诱导表观基因组开关,使得重编程的PNF或SC
易因CDKN 2A和PRC 2的连续丢失而发生恶性转化。我们将决定
NF 1-MPNST形成中发育性Remak口袋缺陷的研究(目的1),研究肿瘤抑制
损伤诱导的重编程SC的机制(目的2),并根据这些机制制定治疗策略。
在重编程SC中损伤诱导表观基因组转换(目的3)。我们将识别损伤引起的和PRC 2-
通过表观基因组方法抑制MPNST形成的致癌驱动因素,开发协同疗法
使用高通量药物再利用筛选,并测试GEM和患者来源的临床前模型。
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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YUAN ZHU其他文献
YUAN ZHU的其他文献
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{{ truncateString('YUAN ZHU', 18)}}的其他基金
Developmental Origin, Injury and Epigenomic Regulation of NF1-Associated Peripheral Nerve Sheath Tumors
NF1相关周围神经鞘肿瘤的发育起源、损伤和表观基因组调控
- 批准号:
10393638 - 财政年份:2021
- 资助金额:
$ 72.33万 - 项目类别:
Developmental Origin, Injury and Epigenomic Regulation of NF1-Associated Peripheral Nerve Sheath Tumors
NF1相关周围神经鞘肿瘤的发育起源、损伤和表观基因组调控
- 批准号:
10599153 - 财政年份:2021
- 资助金额:
$ 72.33万 - 项目类别:
Investigating and targeting pathways of malignant peripheral nerve sheath tumor (MPNST)
恶性周围神经鞘瘤(MPNST)的研究和靶向途径
- 批准号:
10215635 - 财政年份:2019
- 资助金额:
$ 72.33万 - 项目类别:
Investigating and Targeting Pathways of Malignant Peripheral Nerve Sheath Tumor (MPNST)
恶性周围神经鞘瘤 (MPNST) 的研究和靶向途径
- 批准号:
10439466 - 财政年份:2019
- 资助金额:
$ 72.33万 - 项目类别:
Children's Tumor Foundation 2014 Neurofibromatosis (NF) Conference
儿童肿瘤基金会 2014 年神经纤维瘤病 (NF) 会议
- 批准号:
8786019 - 财政年份:2013
- 资助金额:
$ 72.33万 - 项目类别:
Identification of therapeutic windows for NF1-related malignant peripheral nerve
NF1相关恶性周围神经治疗窗口的确定
- 批准号:
8395374 - 财政年份:2012
- 资助金额:
$ 72.33万 - 项目类别:
The role of mTORC1 in the development and therapeutic targeting of NF1-associated
mTORC1 在 NF1 相关疾病的发展和治疗靶向中的作用
- 批准号:
8246412 - 财政年份:2011
- 资助金额:
$ 72.33万 - 项目类别:
The role of mTORC1 in the development and therapeutic targeting of NF1-associated
mTORC1 在 NF1 相关疾病的发展和治疗靶向中的作用
- 批准号:
8423789 - 财政年份:2011
- 资助金额:
$ 72.33万 - 项目类别:
The role of mTORC1 in the development and therapeutic targeting of NF1-associated
mTORC1 在 NF1 相关疾病的发展和治疗靶向中的作用
- 批准号:
8086146 - 财政年份:2011
- 资助金额:
$ 72.33万 - 项目类别:
The role of mTORC1 in the development and therapeutic targeting of NF1-associated
mTORC1 在 NF1 相关疾病的发展和治疗靶向中的作用
- 批准号:
8634151 - 财政年份:2011
- 资助金额:
$ 72.33万 - 项目类别:
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