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
总结
PI 3 K信号传导对于适当的血管生成、新血液的形成和新生血管的形成至关重要。
船舶.然而,异常的PI 3 K信号转导与广泛的血管病变相关。
畸形(VM),包括可能由躯体激活引起的静脉畸形
PIK 3CA突变。VM是正常内皮细胞发育的失败,
分化引起血管功能障碍,使受影响的患者
严重的发病率和经常的毁容。我们的长期目标是更好地了解
血管畸形的分子病因学,希望有助于新的方法,
这些疾病的非手术治疗。我们已经开发了体外和体内模型
的PIK 3CA驱动的VM,并发现mTORC 1轴可能是一个关键组成部分,不适当的
维管形态发生我们的中心假设是mTORC 1轴受到调节,
通过一种新的机制;诱导mTORC 1调节蛋白RHEB。这
该提案旨在确定RHEB在PIK 3CA引起的驾驶畸形中的作用
突变,并揭示了RHEB/mTORC 1轴
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
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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: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
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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: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
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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
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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:6497552
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项目类别:
-
资助金额:$19.01万
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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:6953790
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项目类别:
-
资助金额:$27.73万
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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
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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
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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