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mTOR and VEGFR2 pathways in HHT pathogenesis

HHT 发病机制中的 mTOR 和 VEGFR2 通路

基本信息

批准号：
10652406
负责人：
PHILIPPE MARAMBAUD
金额：
$ 41.88万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-05 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10652406
关键词：
ANGPT1 gene Anemia Angiogenic Factor Angiopoietin-2 Arteriovenous malformation Blood Blood Coagulation Disorders Blood Vessels Cell model Combined Modality Therapy Data Defect Development Disease Dominant Genetic Conditions Drug Targeting ENG gene Endothelial Cells Endothelium FRAP1 gene Gene Abnormality Gene Deletion Gene Expression Profile Genes Genetic Genetic Diseases Genetic Transcription Goals Hemorrhage Hereditary hemorrhagic telangiectasia In Vitro Intervention Investigation KDR gene Knock-in Mouse Knockout Mice Lead Lesion Life Liver Lung Mediating Modeling Mucous Membrane Mus Mutation Organ PIK3CG gene Pathogenesis Pathologic Pathology Pathway interactions Patients Phosphoric Monoester Hydrolases Play Process Property Proteins Receptor Protein-Tyrosine Kinases Receptor Signaling Reporting Repression Retina Retinal Diseases Role Series Signal Transduction Sirolimus Solid TIE-2 Receptor Testing Therapeutic Tissues Tyrosine Kinase Inhibitor angiogenesis autosome clinical investigation derepression design experimental study in vivo loss of function mTOR Inhibitor mTOR inhibition mouse model nintedanib pharmacologic programs public health relevance receptor synergism transcriptome transcriptome sequencing vascular endothelial protein tyrosine phosphatase

项目摘要

PROJECT SUMMARY/ABSTRACT (DESCRIPTION) Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder characterized by the development of systemic and potentially life-threatening vascular anomalies called arteriovenous malformations (AVMs). HHT mutations are mostly found in the ALK1 and ENG genes and lead to a loss-of-function of BMP9/10- ALK1-ENG signaling in endothelial cells (ECs). Recent evidence suggests that HHT pathogenesis and AVM development require the aberrant overactivation of the endothelial mTOR and VEGFR2 pathways. The overall goal of this program is to characterize the precise mechanisms of mTOR and VEGFR2 overactivations upon ALK1-ENG loss-of-function, and determine whether targeting of these mechanisms has disease-modifying properties and therapeutic potential in cell and mouse models of HHT. Using whole-transcriptome interrogation, our preliminary investigation has shown that combined pharmacological inhibition of mTOR and VEGFR2 demonstrated a remarkable synergy and efficacy in correcting a pathological gene expression signature in the BMP9/10-immunoblocked (BMP9/10ib) mouse model of HHT. Strikingly, dual mTOR-VEGFR2 inhibition blocked vascular pathology and AVMs in the retina, liver, lungs, and mucosa to avert bleeding and anemia in BMP9/10ib mice. Mechanistically, our preliminary data revealed that, downstream of ALK1-ENG inhibition, changes in angiopoietin-2 (ANG2)/Tie2 receptor signaling were important triggers for mTOR-VEGFR2 activation and AVM development in HHT mice. Therefore, our data support the working model that HHT pathogenesis is caused by defective ANG2-mTOR-VEGFR2 pathways, and that interventions targeting these mechanistic defects might provide therapeutic benefit in HHT. Based on these results, we propose in Aim 1 to assess whether endothelial mTOR and VEGFR2 are independently activated and whether they are both required for AVM development in HHT mice. To this end, pharmacological and gene deletion approaches independently targeting mTOR and VEGFR2 will be employed in two HHT mouse models: the BMP9/10ib mice and a newly generated knockin (KI) mouse expressing a HHT-causing ALK1 mutation. In Aim 2, we will delineate the precise mechanism of mTOR and VEGFR2 overactivation by ANG2/Tie2 signaling, both in vivo in HHT mice and in vitro in primary ECs, including in HHT patient blood outgrowth ECs. Lastly in Aim 3, we will determine whether Tie2 derepression blocks vascular pathology in HHT mice.

项目摘要/摘要（描述）

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Oxidative stress-induced MMP- and γ-secretase-dependent VE-cadherin processing is modulated by the proteasome and BMP9/10.

DOI：
10.1038/s41598-022-27308-2
发表时间：
2023-01-11
期刊：
Scientific reports
影响因子：
4.6
作者：
通讯作者：

ANG2 Blockade Diminishes Proangiogenic Cerebrovascular Defects Associated With Models of Hereditary Hemorrhagic Telangiectasia.

ANG2阻断可减少与遗传性出血性毛细血管扩张模型相关的促血管生成性脑血管缺陷。

DOI：
10.1161/atvbaha.123.319385
发表时间：
2023
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Zhou,Xingyan;Pucel,JennaC;Nomura-Kitabayashi,Aya;Chandakkar,Pallavi;Guidroz,AdellaP;Jhangiani,NikitaL;Bao,Duran;Fan,Jia;Arthur,HelenM;Ullmer,Christoph;Klein,Christian;Marambaud,Philippe;Meadows,StryderM
通讯作者：
Meadows,StryderM