Molecular Mechanisms Regulating PIK3CA-induced Venous Malformations
Molecular Mechanisms Regulating PIK3CA-induced Venous Malformations
批准号:
10426285
负责人:
KEVIN M PUMIGLIA
金额:
$38.19万
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
项目状态:
未结题
起止时间:
2021-06-10 至 2025-05-31
关键词:
1-Phosphatidylinositol 3-Kinase3-DimensionalAffectAnimal ModelAutomobile DrivingBlood VesselsCandidate Disease GeneCell modelCoupledDevelopmentDiseaseEndothelial CellsEtiologyEvaluationFRAP1 geneFailureGene ExpressionGenesGoalsHumanImmune systemIn Situ HybridizationIn VitroInterventionMetabolicMetabolic PathwayMethodsModelingMolecularMorbidity - disease rateMorphogenesisMutationPIK3CA genePatientsProteinsRNARibosomesRoleSafetySignal TransductionSirolimusTestingVenous Malformationangiogenesisbasecell dimensiongenetic manipulationin vitro Modelin vivoin vivo Modelinsightinsulin sensitivitymalformationnovelnovel strategiesresponsetranscriptomics
中文摘要
摘要
PI3‘-Kinase(PI3K)信号对正常的血管生成、新血的发育至关重要
船只。然而,异常的PI3K信号与广泛的血管
畸形(VM),包括可由躯体激活引起的静脉畸形
PIK3CA基因突变。VMS是内皮细胞正常发育的失败,
分化导致血管功能障碍,使受影响的患者患上
严重的发病率和通常的毁容。我们的长期目标是更好地了解
血管畸形的分子病因学,希望贡献新的方法来治疗
非手术治疗这些疾病的非手术治疗。我们已经开发了体外和体内模型
发现mTORC1轴可能是不正确的关键组件
血管形态发生。我们的中心假设是mTORC1轴正在被调节
通过一种新的机制:mTORC1调节蛋白Rheb的诱导。这
一项旨在确定Rheb在驱动PIK3CA引起的畸形中的作用的提案
突变和揭示Rheb/mTORC1轴机制的分子见解
促进血管畸形的发展。
英文摘要
Summary
PI3’-Kinase (PI3K) signaling is critical for proper angiogenesis, the development of new blood
vessels. However, aberrant PI3K signaling is associated with a wide range of vascular
malformations (VMs), including venous malformations which can arise from somatic activating
mutations in PIK3CA. VMs are failures in proper endothelial cell development and
differentiation giving rise to dysfunctional blood vessels that leave affected patients with
significant morbidity and often disfigurement. Our long-term goal is to better understand the
molecular etiology of vascular malformations with the hope of contributing novel approaches to
the treatment of these conditions non-surgically. We have developed in vitro and in vivo models
of PIK3CA-driven VMs and find that the mTORC1 axis may be a critical component of improper
vascular morphogenesis. Our central hypothesis is that the mTORC1 axis is being regulated
through a novel mechanism; the induction of the mTORC1 regulating protein RHEB. This
proposal seeks to determine the role of RHEB in driving malformations arising from PIK3CA
mutations and reveal molecular insights into the mechanisms by which RHEB/mTORC1 axis
promotes the development of vascular malformations.
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会议论文
Molecular Mechanisms Regulating PIK3CA-induced Venous Malformations
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批准号:10630826
-
项目类别:
-
资助金额:$37.36万
-
财政年份:2021
-
负责人:KEVIN M PUMIGLIA
-
依托单位:
Molecular Mechanisms Regulating PIK3CA-induced Venous Malformations
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批准号:10211277
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项目类别:
-
资助金额:$40.56万
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财政年份:2021
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负责人:KEVIN M PUMIGLIA
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依托单位:
Modulation of Angiogenesis by Regulated Dimerization
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批准号:6321189
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项目类别:
-
资助金额:$15.5万
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财政年份:2001
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负责人:KEVIN M PUMIGLIA
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依托单位:
Modulation of Angiogenesis by Regulated Dimerization
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批准号:6514987
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项目类别:
-
资助金额:$15.5万
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财政年份:2001
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负责人:KEVIN M PUMIGLIA
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依托单位:
Signal Transduction and Tumor Angiogenesis
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批准号:6869051
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项目类别:
-
资助金额:$29.18万
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财政年份:1999
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负责人:KEVIN M PUMIGLIA
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依托单位:
Signal Transduction and Tumor Angiogenesis
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批准号:7238860
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项目类别:
-
资助金额:$29.96万
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财政年份:1999
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负责人:KEVIN M PUMIGLIA
-
依托单位:
Signal Transduction and Tumor Angiogenesis
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批准号:7420953
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项目类别:
-
资助金额:$29.96万
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财政年份:1999
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负责人:KEVIN M PUMIGLIA
-
依托单位:
VEGF SIGNAL TRANSDUCTION AND TUMOR ANGIOGENESIS
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批准号:6350378
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项目类别:
-
资助金额:$18.46万
-
财政年份:1999
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负责人:KEVIN M PUMIGLIA
-
依托单位:
VEGF SIGNAL TRANSDUCTION AND TUMOR ANGIOGENESIS
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批准号:6497552
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项目类别:
-
资助金额:$19.01万
-
财政年份:1999
-
负责人:KEVIN M PUMIGLIA
-
依托单位:
VEGF SIGNAL TRANSDUCTION AND TUMOR ANGIOGENESIS
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批准号:2840379
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项目类别:
-
资助金额:$16.32万
-
财政年份:1999
-
负责人:KEVIN M PUMIGLIA
-
依托单位:
Signal Transduction and Tumor Angiogenesis
-
批准号:6953790
-
项目类别:
-
资助金额:$27.73万
-
财政年份:1999
-
负责人:KEVIN M PUMIGLIA
-
依托单位:
Signal Transduction and Tumor Angiogenesis
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批准号:7116267
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项目类别:
-
资助金额:$30.86万
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财政年份:1999
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负责人:KEVIN M PUMIGLIA
-
依托单位:
VEGF SIGNAL TRANSDUCTION AND TUMOR ANGIOGENESIS
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批准号:6150389
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项目类别:
-
资助金额:$17.92万
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财政年份:1999
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负责人:KEVIN M PUMIGLIA
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依托单位:
LOCALIZATION AND REGULATION OF THE RAF-1 PROTEIN KINASE
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批准号:2112677
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项目类别:
-
资助金额:$2.54万
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财政年份:1996
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负责人:KEVIN M PUMIGLIA
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依托单位:
LOCALIZATION AND REGULATION OF THE RAF-1 PROTEIN KINASE
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批准号:2112676
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项目类别:
-
资助金额:$2.86万
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财政年份:1995
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负责人:KEVIN M PUMIGLIA
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依托单位:
海外基金