EPHB4-RASA1 regulation of lymphatic vessel valve development and function
EPHB4-RASA1对淋巴管瓣膜发育和功能的调节
基本信息
- 批准号:10543485
- 负责人:
- 金额:$ 57.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-04-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AdultApoptosisApoptoticBasement membraneBiologicalBloodBlood CirculationCardiovascular systemCell DeathCell membraneCellsCessation of lifeChylothoraxChylous AscitesCollagen Type IVDataDefectDepositionDevelopmentDiseaseEmbryoEndoplasmic ReticulumEph Family ReceptorsExtravasationFunctional disorderFundingGenesGoalsGrowth Factor ReceptorsGuanosine TriphosphateHealthHumanImmunityImpairmentInheritedIntercellular FluidInvestmentsKnowledgeLaboratoriesLifeLipidsLiquid substanceLymphLymphaticLymphatic CapillariesLymphatic DiseasesLymphatic Endothelial CellsLymphatic functionLymphedemaMaintenanceMedicalMethodologyMissionMolecularMusMuscle CellsMutationOutcomePathway interactionsPatientsPhysiologicalPlayPrevention therapyPublic HealthRas Signaling PathwayReceptor Protein-Tyrosine KinasesRegulationReportingRoleSignal TransductionSignal Transduction PathwaySystemTestingTissuesUnited States National Institutes of HealthVascular SystemVenousVertebratesadaptive immune responsebiological adaptation to stressblindbody cavityburden of illnesscell growthdisabilityexperimental studyinnovationlymph flowlymph nodeslymphatic developmentlymphatic valvelymphatic vesselmouse geneticsnovelnovel therapeuticsvascular factor
项目摘要
The lymphatic vascular system plays an essential role in the transport of interstitial fluid and lipids,
and in the induction of adaptive immune responses in vertebrates. Normal functioning of the lymphatic
vascular system depends upon intraluminal lymphatic valves (LV) that facilitate propulsive flow of
lymph fluid in collecting lymphatic vessels. Defects in LV development and function results in accumu-
lation of lymph in tissues or body cavities resulting in lymphedema, chylothorax and chylous ascites.
From a medical perspective, understanding the molecular mechanisms that regulate the development
and function of LV is critical, yet our knowledge of these mechanisms remains limited. We have re-
ported previously that RASA1, which inhibits activation of the intracellular Ras signal transduction
pathway, is required for the development and maintenance of LV. In addition, others have reported
that the receptor tyrosine kinase, EPHB4, is required for LV development. However, the precise mo-
lecular mechanisms by which RASA1 and EPHB4 regulate LV are unknown. A long-term goal of the
King laboratory is to understand the role of the Ras signaling pathway in different physiological sys-
tems in health and disease. The overall objective of this application, which is consistent with this long-
term goal, is to understand how RASA1 regulates the development and function of LV. Our central
hypothesis is that RASA1, through physical interaction with EPHB4, promotes the export of collagen
IV from LV-forming (LVF) lymphatic endothelial cells (LEC) and mature LEC for deposition in the ex-
tracellular matrix core of developing and established LV leaflets respectively. The rationale for these
studies is that they will inform upon the molecular mechanisms by which RASA1 and EPHB4 regulate
the development and function of LV. We plan to test our central hypothesis and, thereby, attain the
objective of this application by pursuing the following two specific aims: In the first aim, we will use
different molecular cell biologic, mouse genetic, and physiological approaches to understand the mo-
lecular mechanism by which RASA1 loss results in failed development and maintenance of LV. In the
second aim, we will use similar approaches to understand the role of EPHB4 in the development of
LV and the mechanisms involved. The proposed studies are innovative because of the novel method-
ologies employed and the concept that an EPHB4-RASA1 axis is essential for the development and
function of LV acting to export collagen IV from LVF LEC and LV LEC. The studies are significant be-
cause of their potential to lead to new therapies for the prevention and treatment of LV abnormalities
in humans with inherited mutations in RASA1 and EPHB4 genes.
淋巴管系统在间质液和脂质的运输中发挥着重要作用,
以及诱导脊椎动物的适应性免疫反应。淋巴管的正常功能
血管系统依赖于管腔内淋巴管瓣(LV),其促进血液的推进流动。
收集淋巴管中的淋巴液。左心室发育和功能缺陷会导致先天性心脏病,
组织或体腔内的淋巴液流动,导致水肿、乳糜胸和乳糜性腹水。
从医学的角度来看,了解调控发展的分子机制,
左室功能是至关重要的,但我们对这些机制的认识仍然有限。我们已经-
先前报道RASA 1抑制细胞内Ras信号转导的激活,
是LV发展和维持所必需的。此外,还有人报告说,
受体酪氨酸激酶EPHB 4是LV发育所必需的。然而,精确的MO-
RASA 1和EPHB 4调节LV的理论机制尚不清楚。一个长期的目标,
King实验室旨在了解Ras信号通路在不同生理系统中的作用,
健康和疾病的主题。本申请的总体目标,这是符合这一长期-
长期目标是了解RASA 1如何调节LV的发育和功能。我们的中央
假设RASA 1通过与EPHB 4的物理相互作用促进胶原蛋白的输出
IV来自LV形成(LVF)淋巴管内皮细胞(LEC)和成熟LEC,用于在前
分别为发育和建立的LV瓣叶的细胞外基质核心。这些理由
这些研究将为RASA 1和EPHB 4调节的分子机制提供信息。
LV的发育和功能。我们计划测试我们的中心假设,从而达到
通过追求以下两个具体目标来实现本申请的目的:在第一个目标中,我们将使用
不同的分子细胞生物学、小鼠遗传学和生理学方法来了解分子生物学
RASA 1缺失导致LV发育和维持失败的理论机制。在
第二个目标,我们将使用类似的方法来了解EPHB 4在开发中的作用。
LV及其相关机制。所提出的研究是创新的,因为新的方法-
所采用的技术和EPHB 4-RASA 1轴对于开发和
LV从LVF LEC和LV LEC输出胶原IV的功能。这些研究意义重大-
可能导致预防和治疗LV异常的新疗法的原因
RASA 1和EPHB 4基因遗传突变的人。
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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PHILIP D KING其他文献
PHILIP D KING的其他文献
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{{ truncateString('PHILIP D KING', 18)}}的其他基金
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Roles of Macropinocytosis in HIV-1 infection of CD4+ T Cells
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$ 57.12万 - 项目类别:
RASA1-mediated control of lymphatic vessel growth and function
RASA1介导的淋巴管生长和功能控制
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8308412 - 财政年份:2009
- 资助金额:
$ 57.12万 - 项目类别:
RASA1-mediated control of lymphatic vessel growth and function
RASA1介导的淋巴管生长和功能控制
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7688995 - 财政年份:2009
- 资助金额:
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