Erasing ill features of arterial endothelial cells in hereditary hemorrhagic telangiectasia
消除遗传性出血性毛细血管扩张症中动脉内皮细胞的不良特征
基本信息
- 批准号:10413737
- 负责人:
- 金额:$ 39万
- 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:2022-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:ACVRL1 geneArteriesArteriovenous malformationBindingBlood VesselsBypassCell Differentiation processCell LineCell ProliferationChIP-seqCharacteristicsDNA BindingDNA sequencingDataDouble MinutesEndothelial CellsEndotheliumGene DeletionGenetic TranscriptionHereditary hemorrhagic telangiectasiaHomeoboxHumanIn VitroLeadLesionLifeLinkLymphatic EndotheliumMedicalMusNormal tissue morphologyOrganPatientsPersonsPhysiologic arteriovenous anastomosisPublic HealthShunt DeviceSpecificityTelangiectasisTestingTherapeuticTherapeutic InterventionVascular DiseasesVascular Endothelial Growth Factor CVascular Endothelial Growth Factor Receptor-3VeinsWild Type Mouseactivin receptor-like kinase 1capillary bedchromatin immunoprecipitationhigh riskin vivoinhibitorinsightloss of function mutationmouse modelnovelnovel strategiespreventrepaired
项目摘要
PROJECT SUMMARY
Therapeutic advances in vascular disease may have far-reaching public benefits. Arteriovenous malformations
(AVMs) are the common feature of hereditary hemorrhagic telangiectasia (HHT) and cause the high risk of life-
threatening complications. Advanced studies have shown that loss function of mutations in activin receptor-like
kinase 1 (ALK1) are linked to HHT type 2 (HHT2) and ALK1 gene deletion in mice causes AVMs. Previous
studies also reveal that ALK1 is predominantly expressed in arterial endothelial cells (ECs). However, it is
unknown if ALK1 deficiency allows arterial ECs to acquire ill characteristics resulting in AVMs. In present
proposal, we have obtained preliminary data to suggest that the emerging lymphatic endothelial characteristics
in arterial ECs through the induction of mouse double minute 2 (MDM2) is previously unknown mechanism of
AVMs in endothelial ALK1 deficiency, and we show that the approaches of erasing these undesired
characteristics reduce AVMs. Therefore, we hypothesize that ALK1 deficiency elevates MDM2 to cause AVMs
through the induction of lymphatic endothelial characteristics in arterial ECs, and MDM2 inhibition abolishes
these characteristics to reduce AVMs. In specific Aim 1, we will elucidate the mechanism underlying arterial
MDM2 induction as a causative factor of AVMs in endothelial ALK1 deficiency. In specific Aim 2, we will
determine the contribution of arterial MDM2 induction to human HHT2. In specific Aim 3, we will determine if
limiting MDM2 reduces AVMs in endothelial ALK1-deficient mice. There is no primary medical treatment to
prevent or reduce the AVMs of HHT2 patients. In this proposal, we discover a novel mechanism that reveals the
unwanted characteristics emerging in arterial ECs driven by ALK1 deficiency, and arterial ECs with these
characteristics cause AVMs. We identify a compound and propose a novel treatment paradigm aiming to
ameliorate AVMs by erasing these ill characteristics from arterial ECs. If succussed, our proposed studies would
reveal the mechanistic underpinnings of alterations in arterial ECs of HHT2 and provide insight into new
opportunities for therapeutic interventions.
项目总结
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Yucheng Yao其他文献
Yucheng Yao的其他文献
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{{ truncateString('Yucheng Yao', 18)}}的其他基金
Erasing ill features of arterial endothelial cells in hereditary hemorrhagic telangiectasia
消除遗传性出血性毛细血管扩张症中动脉内皮细胞的不良特征
- 批准号:
10586071 - 财政年份:2022
- 资助金额:
$ 39万 - 项目类别:
BMP and Notch crosstalk in cerebral arteriovenous malformations
脑动静脉畸形中的 BMP 和 Notch 串扰
- 批准号:
9381141 - 财政年份:2012
- 资助金额:
$ 39万 - 项目类别:
BMP and Notch Crosstalk in Cerebral Arteriovenous Malformations
脑动静脉畸形中的 BMP 和 Notch 串扰
- 批准号:
8845268 - 财政年份:2012
- 资助金额:
$ 39万 - 项目类别:
BMP and Notch crosstalk in cerebral arteriovenous malformations
脑动静脉畸形中的 BMP 和 Notch 串扰
- 批准号:
10518011 - 财政年份:2012
- 资助金额:
$ 39万 - 项目类别:
BMP and Notch crosstalk in cerebral arteriovenous malformations
脑动静脉畸形中的 BMP 和 Notch 串扰
- 批准号:
9927680 - 财政年份:2012
- 资助金额:
$ 39万 - 项目类别:
BMP and Notch Crosstalk in Cerebral Arteriovenous Malformations
脑动静脉畸形中的 BMP 和 Notch 串扰
- 批准号:
8473295 - 财政年份:2012
- 资助金额:
$ 39万 - 项目类别:
BMP and Notch Crosstalk in Cerebral Arteriovenous Malformations
脑动静脉畸形中的 BMP 和 Notch 串扰
- 批准号:
8666677 - 财政年份:2012
- 资助金额:
$ 39万 - 项目类别:
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