Pulmonary Hypertension in Left Heart Disease
Pulmonary Hypertension in Left Heart Disease
批准号:
10656879
负责人:
Barry A. Borlaug
金额:
$80.35万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-06-01 至 2028-05-31
关键词:
AddressAdultAerobicAnatomyAnimal ModelAutopsyBackBioinformaticsBiologicalBiologyBlood VesselsBlood capillariesCirculationClassificationClinicalDataDiseaseEpidemiologyExertionFRAP1 geneFunctional disorderGleanGoalsHeart DiseasesHistologicHumanKnowledgeLeftLife ExpectancyLinkLocalized DiseaseLocationLungLung diseasesMass Spectrum AnalysisMediatingMiniature SwineMorbidity - disease rateNatureNeonatalOutcome StudyOutcomes ResearchPathway interactionsPatientsPhenotypePrognosisProteinsProteomicsPulmonary Heart DiseasePulmonary HypertensionPulmonary Vascular ResistancePulmonary arterial remodelingResearchRho-associated kinaseSeveritiesSignal TransductionSirolimusStructure of parenchyma of lungSymptomsSystemTechniquesTerminologyTherapeuticTherapeutic AgentsVascular remodelingVenousVentricularWorkdifferential expressioneffective therapyfasudilhemodynamicsindividualized medicineinnovationkinase inhibitorlaser capture microdissectionmortalitynovelnovel strategiesnovel therapeuticsporcine modelpressureprogramspulmonary arterial hypertensionpulmonary arterial pressurepulmonary vascular disorderpulmonary venous hypertensionresponseright ventricular failurestemsymptomatic improvementtherapeutic targettranscriptomicstreatment responsevasoconstriction
中文摘要
项目总结/摘要
左心疾病(LHD)导致肺动脉高压(PH-LHD,又名第2组PH)、右心室(RV)
失败,并增加死亡率和发病率。肺血管生物学研究进展
第1组PH和相关动物模型中的肺动脉(PA)循环导致了有效的治疗方法
在PH-LHD中进行的第1组PH治疗试验显示出高度可变(有利、中性或
有害的)影响。我们认为,两个关键的知识差距有助于治疗反应的变异性
并阻碍了PH-LHD治疗的进展:(1)缺乏机械信息的血流动力学
定义性质(血管收缩与重塑)和位置(PA与肺静脉)的分类系统
(PV))LHD中肺血管疾病的发生率,以及(2)缺乏对血管特异性(PV vs PA)的了解
PH-LHD中介导肺血管疾病的生物学途径。这项建议的目的是
解决这些知识差距,并实现PH-LHD的治疗创新。根据广泛的初步
在人类和实验性(Exp)PH-LHD研究中,我们的中心假设是PH-LHD是一种表型
不同的实体,其最终治疗方法将由独特的血流动力学表型定义,
血管特异性(PA vs PV)病理生理学扰动。在人类和实验PH-LHD中,我们将使用新的
根据肺血管阻力(PVR)对表型PH-LHD进行血流动力学评估,
血管反应性和PVR的纵向分布(目的1)。将通过以下方法在人PH-LHD中验证结果:
评估有氧能力、RV储备功能和劳力肺的表型组特异性差异
拥堵将通过定义PA和PV重塑(定量)来验证Exp PH-LHD中的结果
组织形态测定法)。我们广泛的假设是,PVR升高的主要机制和位置
具有临床意义和解剖学基础。在人类和实验性PH-LHD中,我们将
(Aim 2)使用基于组织化学、蛋白质组学和转录组学的技术和生物信息学分析来定义
跨PH-LHD表型组的血管特异性机制。这些研究将结合Aim 1血流动力学
血管特异性血管生物学的表型分析方法。在目标3中,我们将确定是否基于
在我们的人类组学研究中,实验PH-LHD将改善PV或PA重塑并延缓进展,
在早期或晚期Exp PH-LHD表型组中的PH。这项工作的研究成果将是一个新的
PH-LHD的血流动力学分类与特定的病理生理学和治疗靶点相关,因此能够
个体化治疗方法。
英文摘要
PROJECT SUMMARY / ABSTRACT
Left heart disease (LHD) leads to pulmonary hypertension (PH-LHD, aka Group 2 PH), right ventricular (RV)
failure, and increased mortality and morbidity. Advances in pulmonary vascular biology gleaned from study of
the pulmonary arterial (PA) circulation in Group 1 PH and relevant animal models have led to effective therapies
for Group 1 PH. Trials of Group 1 PH therapies in PH-LHD have shown highly variable (favorable, neutral or
harmful) effects. We propose that two critical knowledge gaps contribute to variability in therapeutic response
and impede progress in treating PH-LHD: (1) the lack of a mechanistically informative hemodynamic
classification system defining the nature (vasoconstriction vs remodeling) and location (PA vs pulmonary venous
(PV)) of pulmonary vascular disease in LHD, and (2) lack of understanding of vessel specific (PV vs PA)
biological pathways mediating pulmonary vascular disease in PH-LHD. The objective of this proposal is to
address these knowledge gaps and enable therapeutic innovation in PH-LHD. Based on extensive preliminary
studies in human and experimental (Exp) PH-LHD, our central hypothesis is that PH-LHD is a phenotypically
diverse entity whose ultimate therapeutic approach will be defined by unique hemodynamic phenogroups and
vessel specific (PA vs PV) pathophysiological perturbations. In human and Exp PH-LHD, we will use novel
hemodynamic assessments to phenotype PH-LHD according to pulmonary vascular resistance (PVR),
vasoreactivity, and the longitudinal distribution of PVR (Aim 1). Findings will be validated in human PH-LHD by
assessing phenogroup-specific differences in aerobic capacity, RV reserve function and exertional lung
congestion. Findings in Exp PH-LHD will be validated by defining PA and PV remodeling (quantitative
histomorphometry). Our broad hypothesis is that both the primary mechanism and location of the elevated PVR
in PH-LHD have clinical implications and anatomical underpinnings. In human and Exp PH-LHD, we will then
(Aim 2) use histochemical, proteomic, and transcriptomic based techniques and bioinformatic analyses to define
vessel specific mechanisms across PH-LHD phenogroups. These studies will couple the Aim 1 hemodynamic
phenotyping approach to vessel specific vascular biology. In Aim 3, we will determine if therapeutic agents based
on our omics studies in human and Exp PH-LHD will ameliorate PV or PA remodeling and delay the progression
of PH in Early or Late Exp PH-LHD phenogroups. The research outcome from this work will be a new
hemodynamic classification of PH-LHD linked to specific pathophysiology and therapeutic targets, thus enabling
individualized medicine approaches to PH-LHD.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Mayo Clinic HeartShare Clinical Center
-
批准号:10679096
-
项目类别:
-
资助金额:$28.1万
-
财政年份:2021
-
负责人:Barry A. Borlaug
-
依托单位:
Mayo Clinic HeartShare Clinical Center
-
批准号:10323121
-
项目类别:
-
资助金额:$28.08万
-
财政年份:2021
-
负责人:Barry A. Borlaug
-
依托单位:
Mayo Clinic HeartShare Clinical Center
-
批准号:10483137
-
项目类别:
-
资助金额:$28.1万
-
财政年份:2021
-
负责人:Barry A. Borlaug
-
依托单位:
HL-Inorganic Nitrite to Enhance Benefits from Exercise Training in Heart Failure with preserved Ejection Fraction
-
批准号:9252549
-
项目类别:
-
资助金额:$58.75万
-
财政年份:2016
-
负责人:Barry A. Borlaug
-
依托单位:
HL-Inorganic Nitrite to Enhance Benefits from Exercise Training in Heart Failure with preserved Ejection Fraction
-
批准号:9459406
-
项目类别:
-
资助金额:$58.75万
-
财政年份:2016
-
负责人:Barry A. Borlaug
-
依托单位:
海外基金