Pathogenic Mechanisms of Pulmonary Lymphangioleiomyomatosis
肺淋巴管平滑肌瘤病的发病机制
基本信息
- 批准号:10371888
- 负责人:
- 金额:$ 34.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2022-09-30
- 项目状态:已结题
- 来源:
- 关键词:Abnormal CellAddressAdultAllograftingBiologyCellsCessation of lifeChIP-seqClinicalComplexCystDataDefectDependenceDevelopmentEmbryoEnhancersEstrogen Receptor alphaEstrogen Receptor betaEstrogensFRAP1 geneFemaleGenderGeneticGenetically Engineered MouseGestational AgeHeterogeneityHomeostasisHumanImpairmentIn VitroInvestigationKnock-outKnockout MiceKnowledgeLeadLesionLungLung LymphangioleiomyomatosisLung noduleLymphangioleiomyomatosisMediatingMesenchymalMesenchymeMetabolicMetabolic dysfunctionMetabolismMitochondriaModelingMolecularMorbidity - disease rateMusMutationNodular LesionNoduleNull LymphocytesOxygenParabiosisPathogenesisPathogenicityPharmacologyPneumothoraxProteinsPulmonary PathologyReactive Oxygen SpeciesResearchRespiratory physiologyRoleSignal TransductionSmooth MuscleStructure of parenchyma of lungStudy modelsTSC1 geneTSC2 geneTherapeuticTimeTuberous SclerosisTuberous sclerosis protein complexWomancell growthcell typegenetic approachhormonal signalsin vivoloss of function mutationlung lesionmelanocytemenmitochondrial dysfunctionmortalitymouse modelnovelpre-clinicalpublic health relevancerecruitreverse geneticstranscriptome sequencingtranslational impact
项目摘要
Project Summary/Abstract
Lymphangioleiomyomatosis (LAM), characterized by nodular proliferation of abnormal smooth muscle-
like cells (LAM cells) and pulmonary cysts, is a significant cause of morbidity and mortality in women with
Tuberous Sclerosis Complex (TSC) or with the sporadic form of LAM. LAM is associated with genetic
inactivation of TSC1 or TSC2. Critical knowledge gaps include the heterogeneity of cells within LAM nodules,
the cellular origin of TSC2-deficient LAM cells, and mechanisms underlying the female predominance of LAM.
Early developmental deletion of Tsc2 (E6.5-E14.5) in lung mesenchyme resulted in nodular pulmonary
lesions in adulthood, predominantly in female mice. These proliferative nodules are composed of cells with loss
of Tsc2 as well as wild-type cells, resembling human LAM nodules. The nodules contain cells expressing
smooth muscle and melanocyte lineage proteins, hallmarks of human LAM. Later developmental deletion of
Tsc2 (E13.5-P1), sparing the pulmonary vasculature, does not result in pulmonary nodular lesions in
adulthood. Metabolic and mitochondrial defects are present in Tsc2-null mesenchymal cells derived from the
pulmonary nodules, compared with wild-type controls. Estrogen stimulates proliferation of these Tsc2-null cells,
but not wild-type cells, and upregulates mitochondrially-derived reactive oxygen species. These and other
preliminary data lead to our central hypothesis: hyperactivation of mTORC1 in subsets of lung mesenchymal
cells leads to estrogen-dependent proliferation of nodular-like lesions, associated with metabolic and
mitochondrial dysfunction, recruitment of extrapulmonary cells and lung destruction.
Two specific aims are proposed: 1) To dissect the molecular and cellular mechanisms of LAM using a
novel mouse model with spontaneous LAM-like lung lesions. The role of hyperactivated mTORC1 in the
pulmonary LAM-like nodules will be examined using both pharmacologic and genetic approaches. The impact
of Tsc2 deficiency on cellular metabolism and mitochondrial function will be addressed for the first time in lung
mesenchyme-derived cells as a potential mechanism for the abnormal cell growth. The origin of LAM cells and
the mechanisms of recruitment of extrapulmonary mesenchymal cells to LAM-like nodules will be examined
using both parabiosis and allograft models. 2) To determine the specific role of gender in contributing to the
formation and progression of LAM-like nodules in mice with lung mesenchymal Tsc2 deletion. The roles of
estrogen in the pulmonary LAM-like lesions will be investigated in vivo by altering estrogen activity or
simultaneous deletion of ERα/Tsc2 or ERβ/Tsc2 and in vitro by metabolic profiling, RNA-seq, ChIP-seq in
Tsc2-null vs. wild-type cells. This project will have high scientific and clinical impact by filling knowledge
gaps with translational impact for women with LAM and providing a new preclinical therapeutic model.
项目概要/摘要
淋巴管平滑肌瘤病 (LAM),其特征是异常平滑肌的结节性增殖
细胞(LAM细胞)和肺囊肿,是患有以下疾病的女性发病和死亡的重要原因
结节性硬化症 (TSC) 或散发性 LAM 与遗传有关。
TSC1 或 TSC2 失活的关键知识差距包括 LAM 结节内细胞的异质性,
TSC2 缺陷型 LAM 细胞的细胞起源,以及 LAM 女性优势的潜在机制。
肺间充质中 Tsc2 (E6.5-E14.5) 的早期发育缺失导致结节性肺
成年期的病变,主要发生在雌性小鼠中,这些增殖性结节由丢失的细胞组成。
Tsc2 以及野生型细胞,类似于人类 LAM 结节,结节含有表达细胞。
平滑肌和黑素细胞谱系蛋白,人类 LAM 的后期发育缺失的标志。
Tsc2 (E13.5-P1) 不影响肺血管系统,不会导致肺部结节性病变
成年期,来自 Tsc2 缺失的间充质细胞存在代谢和线粒体缺陷。
与野生型对照相比,雌激素刺激这些 Tsc2 缺失细胞的增殖,
但野生型细胞则不然,并且上调线粒体衍生的活性氧。
初步数据得出我们的中心假设:肺间充质亚群中 mTORC1 过度激活
细胞导致结节样病变的雌激素依赖性增殖,与代谢和
线粒体功能障碍、肺外细胞募集和肺破坏。
提出了两个具体目标:1)使用
具有自发性 LAM 样肺部病变的新型小鼠模型 过度激活的 mTORC1 在
将使用药理学和遗传学方法检查肺部 LAM 样结节的影响。
Tsc2 缺乏对细胞代谢和线粒体功能的影响将首次在肺中得到解决
间质来源的细胞作为异常细胞生长的潜在机制。
将检查肺外间充质细胞募集至 LAM 样结节的机制
使用联体共生和同种异体移植模型 2) 确定性别在促进
肺间质 Tsc2 缺失小鼠 LAM 样结节的形成和进展。
肺部 LAM 样病变中的雌激素将通过改变雌激素活性或
通过代谢分析、RNA-seq、ChIP-seq 在体外同时删除 ERα/Tsc2 或 ERβ/Tsc2
Tsc2-null 细胞与野生型细胞的对比 该项目将通过补充知识产生巨大的科学和临床影响。
差距对患有 LAM 的女性产生转化影响,并提供新的临床前治疗模式。
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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Elizabeth P Henske其他文献
Elizabeth P Henske的其他文献
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{{ truncateString('Elizabeth P Henske', 18)}}的其他基金
Mechanisms of immunosuppression in the development and progression of renal disease in Tuberous Sclerosis Complex
免疫抑制在结节性硬化症肾病发生和进展中的机制
- 批准号:
10658079 - 财政年份:2023
- 资助金额:
$ 34.14万 - 项目类别:
Role of the Lysosome in the Pathogenesis and Therapy of LAM
溶酶体在 LAM 发病机制和治疗中的作用
- 批准号:
10214679 - 财政年份:2020
- 资助金额:
$ 34.14万 - 项目类别:
Role of the Lysosome in the Pathogenesis and Therapy of LAM
溶酶体在 LAM 发病机制和治疗中的作用
- 批准号:
10633178 - 财政年份:2020
- 资助金额:
$ 34.14万 - 项目类别:
Role of the Lysosome in the Pathogenesis and Therapy of LAM
溶酶体在 LAM 发病机制和治疗中的作用
- 批准号:
10431886 - 财政年份:2020
- 资助金额:
$ 34.14万 - 项目类别:
Pathogenic Mechanisms of Pulmonary Lymphangioleiomyomatosis
肺淋巴管平滑肌瘤病的发病机制
- 批准号:
9900580 - 财政年份:2019
- 资助金额:
$ 34.14万 - 项目类别:
The Metabolic Pathogenesis of Chromophobe Renal Cell Carcinoma
嫌色肾细胞癌的代谢发病机制
- 批准号:
10079018 - 财政年份:2018
- 资助金额:
$ 34.14万 - 项目类别:
The Metabolic Pathogenesis of Chromophobe Renal Cell Carcinoma
嫌色肾细胞癌的代谢发病机制
- 批准号:
10322414 - 财政年份:2018
- 资助金额:
$ 34.14万 - 项目类别:
The Molecular and Genetic Pathogenesis of LAM
LAM 的分子和遗传发病机制
- 批准号:
10563145 - 财政年份:2016
- 资助金额:
$ 34.14万 - 项目类别:
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