Molecular pathogenesis of pulmonary arterial hypertension
肺动脉高压的分子发病机制
基本信息
- 批准号:10211271
- 负责人:
- 金额:$ 80.37万
- 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
- 起止时间:2021-05-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:Animal ModelAttenuatedBlood CellsBlood VesselsBone Morphogenetic ProteinsCell physiologyCellsCessation of lifeDNA DamageDNA Double Strand BreakDNA RepairDNA Repair PathwayDiseaseDistalEndotheliumEtiologyGenesGeneticGenomic InstabilityGenotoxic StressGoalsHeart failureHeritabilityHomeostasisHumanKnowledgeLightLinkLungMaintenanceMeasuresMediatingMessenger RNAMolecularMorbidity - disease rateMutationOther GeneticsPathogenesisPathologicPatientsPenetranceProgressive DiseasePulmonary artery structureRare DiseasesReceptor GeneRegulationReportingRisk FactorsRoleSignal PathwaySignal TransductionSomatic MutationSystemTestingTranslatingTransplantationVascular DiseasesVascular remodelingVentricularattenuationbone morphogenetic protein receptorscell typegenome integritygenotoxicityhigh riskhomologous recombinationinsightmortalitymutation carriernovel therapeutic interventionnovel therapeuticspreventprimary pulmonary hypertensionprotein degradationpulmonary arterial hypertensionpulmonary artery endothelial celltargeted treatment
项目摘要
PROJECT SUMMARY/ABSTRACT
Pulmonary Arterial Hypertension (PAH) is a rare disease characterized by the progressive remodeling of
pulmonary arteries (PAs). It is incurable and leads to death from right ventricular heart failure in 3 years if
untreated. Heterozygous mutations of the bone morphogenetic protein type 2 receptor gene (BMPR2) are the
leading genetic cause of both heritable and non-heritable PAH. Compared to patients without BMPR2
mutations, PAH patients with BMPR2 mutations develop a more severe form of PAH at least 10 years earlier.
Despite the progress in understanding the molecular and cellular processes mediating occlusive remodeling of
PAs as a result of BMPR2 mutations, a targeted therapy does not yet exist, and BMPR2 carrier patients remain
at high risk of requiring transplantation and succumbing to the disease. There is a dire need of novel therapies
for BMPR2 mutation patients.
Our studies demonstrated increased DNA damage in both idiopathic- and heritable-PAH patients,
suggesting genotoxic stress is a risk factor for PAH, but significant knowledge gaps persist, as follows: (i)
whether the loss of genome integrity is the cause or the consequence of PAH, (ii) the cell type in which DNA
damage occur, (iii) a potential link between BMPR2 mutations and DNA damage, and (iv) the molecular
mechanism of DNA damage in PAH. We found that BMPR2 and its downstream signaling pathway are
essential to protect genome integrity in pulmonary artery endothelial cells (PAECs), and they act by
maintaining a key component of the DNA repair pathway: Rad51. Inactivation of BMPR2 results in reduction of
Rad51, leading to accumulation of DNA damage in PAECs. Attenuation of Rad51 was measured in the
endothelium of both animal models of PAH and human patients. On the contrary, activation of the BMPR2
signaling pathway by BMP9 restores Rad51 and prevents the accumulation of DNA damage in PAECs. The
main hypothesis we will test is that PAECs undergoing genotoxic stress develop a pathological remodeling and
PAH. The objective of this application is to develop a strategy to restore the DNA repair system in PAECs and
prevent or inhibit the progression of vascular remodeling, as a novel therapy for PAH with a defective BMP
signal. The forthcoming results from this application will provide important insights into developing a novel
therapeutic strategy for PAH.
项目摘要/摘要
肺动脉高压(PAH)是一种罕见疾病,其特征是进行性重塑
肺动脉(PAS)。它是无法治愈的,如果在3年内右心室心力衰竭导致死亡
未经处理。骨形态发生蛋白2受体基因(BMPR2)的杂合突变是
可遗传和不可遗忘的PAH的主要遗传原因。与没有BMPR2的患者相比
突变,BMPR2突变的PAH患者至少在10年前会形成更严重的PAH。
尽管在理解分子和细胞过程方面取得了进展,介导的闭塞重塑
BMPR2突变的结果,尚不存在靶向疗法,而BMPR2载体患者仍然存在
有需要移植和屈服于该疾病的高风险。迫切需要新颖的疗法
对于BMPR2突变患者。
我们的研究表明,特发性和可遗传性PAH患者的DNA损伤增加了,
暗示遗传毒性应激是PAH的危险因素,但是大量知识差距持续存在,如下所示:(i)
基因组完整性的丧失是PAH的原因还是后果,(ii)DNA的细胞类型
发生损坏,(iii)BMPR2突变与DNA损伤之间的潜在联系,以及(iv)分子
PAH中DNA损伤的机理。我们发现BMPR2及其下游信号通路是
保护肺动脉内皮细胞(PAEC)中的基因组完整性至关重要
维持DNA修复途径的关键组件:RAD51。 BMPR2的失活导致减少
RAD51,导致PAEC中DNA损伤的积累。在
PAH和人类患者动物模型的内皮。相反,激活BMPR2
BMP9的信号通路可恢复RAD51并防止DNA损伤在PAEC中的积累。这
主要假设我们将检验
pah。该应用的目的是制定恢复PAEC中DNA维修系统的策略,并
预防或抑制血管重塑的进展,作为对BMP缺陷的PAH的新疗法
信号。该应用程序的即将到来的结果将为开发小说提供重要的见解
PAH的治疗策略。
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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Akiko Hata其他文献
Akiko Hata的其他文献
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{{ truncateString('Akiko Hata', 18)}}的其他基金
Elucidating the structural insights into the BMP receptor mutations in PAH
阐明 PAH 中 BMP 受体突变的结构见解
- 批准号:
10659947 - 财政年份:2023
- 资助金额:
$ 80.37万 - 项目类别:
Molecular pathogenesis of pulmonary arterial hypertension
肺动脉高压的分子发病机制
- 批准号:
10400195 - 财政年份:2021
- 资助金额:
$ 80.37万 - 项目类别:
Molecular pathogenesis of pulmonary arterial hypertension
肺动脉高压的分子发病机制
- 批准号:
10560621 - 财政年份:2021
- 资助金额:
$ 80.37万 - 项目类别:
Identification of a novel modulator of Pulmonary Artery Hypertension
一种新型肺动脉高压调节剂的鉴定
- 批准号:
9088922 - 财政年份:2016
- 资助金额:
$ 80.37万 - 项目类别:
Identification of a novel modulator of Pulmonary Artery Hypertension
一种新型肺动脉高压调节剂的鉴定
- 批准号:
9282758 - 财政年份:2016
- 资助金额:
$ 80.37万 - 项目类别:
Role of the PDGF signaling pathway in pulmonary artery hypertension
PDGF信号通路在肺动脉高压中的作用
- 批准号:
8461453 - 财政年份:2013
- 资助金额:
$ 80.37万 - 项目类别:
Role of the PDGF signaling pathway in pulmonary artery hypertension
PDGF信号通路在肺动脉高压中的作用
- 批准号:
8714040 - 财政年份:2013
- 资助金额:
$ 80.37万 - 项目类别:
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