Pathogenesis and Treatment of Kaposiform Lymphangiomatosis
卡波西样淋巴管瘤病的发病机制及治疗
基本信息
- 批准号:10544755
- 负责人:
- 金额:$ 61.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAbdomenAffectAngiogenic FactorAngiopoietin-2AntibodiesAutomobile DrivingBiological AssayBiological MarkersBiopsyBloodBlood Coagulation DisordersBlood VesselsCardiacCellsCellular MorphologyCharacteristicsChemicalsChestChildClinicalClinical TrialsComplexCystCytoplasmCytoplasmic GranulesDNA Sequence AlterationDataDiagnosisDietDiseaseDoxycyclineEndothelial CellsErythrocytesExperimental ModelsFRAP1 geneFilmFunctional disorderGeneticGoalsHandHemorrhageHemosiderinHistologyHistopathologyHumanImageImplantIn VitroInvadedKnowledgeLaboratoriesLeftLesionLiverLungLymphangiogenesisLymphangiographyLymphangiomatosisLymphaticMAP Kinase GeneMEKsMagnetic Resonance ImagingMalignant NeoplasmsManuscriptsMeasuresMediatingMediatorModelingMolecularMorbidity - disease rateMorphogenesisMusMutationNeuroblastomaOrganPIK3CG genePathogenesisPathway interactionsPatientsPhosphotransferasesPleuralPleural effusion disorderPositioning AttributePre-Clinical ModelProcessProliferatingProteomicsProto-Oncogene Proteins c-aktPulmonary artery structureRadiology SpecialtyRecurrent diseaseRegulationRetroperitoneal SpaceRiskRoleShapesSignal PathwaySignal TransductionSirolimusSomatic MutationSpindle Endothelial CellSpleenStainsStructureSymptomsTEK geneTailTestingTissuesUnited States National Institutes of HealthVeinsXenograft ModelXenograft procedureautocrineeffusionexperiencefeedingin vitro Modelin vivo Modelinhibitorinsightlymphatic malformationslymphatic vesselmTOR Inhibitormalformationmelanomamigrationmortalitymutantnew therapeutic targetnovel therapeuticsoverexpressionparacrineresponsesmall hairpin RNAsoft tissuesubcutaneoustranscriptome sequencingyoung adult
项目摘要
Kaposiform lymphangiomatosis (KLA) is a devastating congenital lymphatic anomaly with a 51% survival at
5 years, and 34% overall. KLA patients suffer from pleural and cardiac effusions and coagulopathy leading to
the high morbidity and mortality. The histopathology of KLA features lesions containing clusters of spindle-
shaped endothelial cells accompanying malformed lymphatic vessels typically in the lungs, spleen, abdomen,
and/or liver. The role, origin and function of these characteristic spindled endothelial cells is unclear. Definitive
diagnosis of KLA is often delayed due to the complex symptoms and the risks of biopsy due to the
coagulopathy. As part of a clinical trial using sirolimus (rapamycin; mTOR inhibitor) we were the first to identify
a blood biomarker for KLA, angiopoietin-2 (ANG-2), that may provide important insights into the underlying
disease mechanisms. ANG-2, which can act as a pro-angiogenic factor, was highly elevated in KLA patients
and decreased with sirolimus treatment suggesting that dysregulation of ANG-2 in KLA is dependent on
mTOR signaling. Additional possible insights into pathogenesis of KLA have come from the identification of a
somatic mutation NRAS Q61R in lesion tissue from patients. Q61R is an NRAS activating mutation in >20%
of melanomas and other cancers; however, its role in human endothelial cells and vascular malformations is
unclear. Our preliminary studies with human endothelial cells suggest that NRAS Q61R is upstream of ANG-
2 and induces the spindled endothelial cell morphology in KLA lesions. Proposed studies will identify the
processes and pathways involved in this regulation and help move the understanding of KLA pathogenesis
forward. The goal of this proposal is to test the hypothesis that NRAS Q61R mediates the pathogenesis
of KLA by increasing MAPK and PI3K-AKT-mTOR signaling, inducing spindled endothelial cells,
upregulating ANG-2 expression, and so driving abnormal lymphangiogenesis. We have developed
unique in vitro and in vivo models to test this hypothesis and preliminary data from our laboratory strongly
supports this proposed mechanism and demonstrates the feasibility of our approach. These studies will
address a critical knowledge gap in KLA. We will test new therapeutic targets since the current treatment,
sirolimus, at best only induces a partial clinical response. Our long-term goals are to elucidate the cellular and
molecular pathogenesis of KLA and identify new therapeutic targets. We are uniquely positioned having the
expertise and experimental models in hand.
卡波西样淋巴管瘤病 (KLA) 是一种破坏性的先天性淋巴管异常,其存活率为 51%
5 年,总体 34%。 KLA 患者患有胸腔积液和心脏积液以及凝血障碍,导致
高发病率和死亡率。 KLA 的组织病理学特征是含有纺锤体簇的病变。
畸形的内皮细胞伴随着畸形的淋巴管,通常出现在肺、脾、腹部、
和/或肝脏。这些特征性梭形内皮细胞的作用、起源和功能尚不清楚。权威的
由于复杂的症状和活检的风险,KLA 的诊断经常被延迟
凝血病。作为使用西罗莫司(雷帕霉素;mTOR 抑制剂)临床试验的一部分,我们是第一个发现
KLA 血管生成素-2 (ANG-2) 的血液生物标志物,可能为了解潜在的疾病提供重要见解
疾病机制。 ANG-2 可以作为促血管生成因子,在 KLA 患者中高度升高
并随西罗莫司治疗而减少,表明 KLA 中 ANG-2 的失调取决于
mTOR 信号传导。对 KLA 发病机制的更多可能见解来自于对
患者病变组织中的体细胞突变 NRAS Q61R。 Q61R 是 >20% 的 NRAS 激活突变
黑色素瘤和其他癌症;然而,它在人类内皮细胞和血管畸形中的作用是
不清楚。我们对人内皮细胞的初步研究表明 NRAS Q61R 是 ANG- 的上游
2并诱导KLA损伤中的梭形内皮细胞形态。拟议的研究将确定
参与该调节的过程和途径,有助于加深对 KLA 发病机制的理解
向前。该提案的目的是检验 NRAS Q61R 介导发病机制的假设
通过增加 MAPK 和 PI3K-AKT-mTOR 信号传导,诱导梭形内皮细胞,
上调 ANG-2 表达,从而驱动异常淋巴管生成。我们开发了
独特的体外和体内模型有力地检验了这一假设以及我们实验室的初步数据
支持这一提议的机制并证明了我们方法的可行性。这些研究将
解决 KLA 中的关键知识差距。自目前的治疗以来,我们将测试新的治疗靶点,
西罗莫司最多只能引起部分临床反应。我们的长期目标是阐明细胞和
KLA 的分子发病机制并确定新的治疗靶点。我们处于独特的地位,拥有
现有的专业知识和实验模型。
项目成果
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TIMOTHY DAVID LE CRAS其他文献
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{{ truncateString('TIMOTHY DAVID LE CRAS', 18)}}的其他基金
Pathogenesis and Treatment of Kaposiform Lymphangiomatosis
卡波西样淋巴管瘤病的发病机制及治疗
- 批准号:
10360838 - 财政年份:2022
- 资助金额:
$ 61.83万 - 项目类别:
Role of TGF-Alpha in Pulmonary Vascular Disease
TGF-α 在肺血管疾病中的作用
- 批准号:
6597898 - 财政年份:2003
- 资助金额:
$ 61.83万 - 项目类别:
Role of TGF-Alpha in Pulmonary Vascular Disease
TGF-α 在肺血管疾病中的作用
- 批准号:
6733597 - 财政年份:2003
- 资助金额:
$ 61.83万 - 项目类别:
Role of TGF-Alpha in Pulmonary Vascular Disease
TGF-α 在肺血管疾病中的作用
- 批准号:
7022907 - 财政年份:2003
- 资助金额:
$ 61.83万 - 项目类别:
Role of TGF-Alpha in Pulmonary Vascular Disease
TGF-α 在肺血管疾病中的作用
- 批准号:
6874946 - 财政年份:2003
- 资助金额:
$ 61.83万 - 项目类别:
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