Clinical and mechanistic role of HDGF in pulmonary hypertension
Clinical and mechanistic role of HDGF in pulmonary hypertension
批准号:
9772631
负责人:
ALLEN D EVERETT
金额:
$27.2万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-01-01 至 2020-12-31
关键词:
Activities of Daily LivingAddressAdministrative SupplementAdultAffectAgeAngiogenesis InhibitorsAngiogenic ProteinsAwardBMPR2 geneBenchmarkingBiological AssayBiological MarkersBlood VesselsCAV1 geneCell LineCell ProliferationCellsChildChildhoodChromosomes, Human, Pair 21ClinicClinicalClinical ResearchCollaborationsCollagenColoradoComorbidityCustomDataDefectDevelopmentDiagnosticDiseaseDown SyndromeEchocardiographyEndostatinsEtiologyEventFundingFutureGenesGenomicsGoalsHarvestHeart failureHumanIL6 geneIn VitroIncidenceInflammationLinkLungMeasuresMediatingMitogensMorbidity - disease rateNational Heart, Lung, and Blood InstituteOutcomeParentsPathway interactionsPatientsPatternPhenotypePhosphorylationPrognostic MarkerProteomicsPulmonary HypertensionPulmonary artery structureResearchRiskRoleSamplingSensitivity and SpecificitySerumSeveritiesSignal PathwaySmooth MuscleSmooth Muscle MyocytesStimulation of Cell ProliferationSystemic diseaseTestingUniversitiesValidationVascular Endothelial Growth FactorsVasodilator AgentsWalkingangiogenesisbiobankbiomarker panelburden of illnesscirculating biomarkersclinical practicecohortcongenital heart disorderdefined contributionexperimental studyfactor Afunctional outcomesgenetic varianthemodynamicshepatoma-derived growth factorimproved outcomein vivoinnovationinsightminimally invasivemortalitymutantnew therapeutic targetnovel therapeuticsoutcome forecastpressureprognosticpulmonary arterial hypertensionresponsesuccesssurvival outcomesurvival predictiontherapeutic targettreatment responsevasculogenesis
中文摘要
儿童或成人的肺动脉高压(PH)是一种进行性和致命性疾病,其特征是持续的肺动脉高压。
病因不明的肺动脉压升高。尽管血管扩张药物的数量
增加,仍然有20-30%的患者没有反应,无反应者最终预后不良
需要肺移植1 -4.肺动脉高压是唐氏综合征的常见病因
并与死亡率增加有关,特别是在先天性心脏病(CHD)患者中。
在科罗拉多大学唐氏综合征诊所,27.6%的患者患有肺动脉高压。
肺动脉高压增加唐氏综合征患者的发病率和死亡率,
疾病负担和增加肺动脉高压风险的特定合并症的作用
在唐氏综合症中的作用还没有完全被理解。9一个主要原因,是我们缺乏简单、微创的治疗方法,
Down患者肺/血管特异性、客观、可重复、可推广且成本较低的PH测量
综合征,以改善预后。研究,“HDGF在肺动脉高压中的临床和机制作用”
R 01 HL 135114 -02由国家心肺和血液研究所授予,旨在阐明体外和
HDGF在I组肺动脉高压中体内机制作用和作为循环因子的潜力
PAH严重程度、治疗反应和生存率的新指标。
通过这项研究,我们与大学的NHLBI PAHBiobank建立了合作关系。
范德比尔特大学和科罗拉多大学的丹佛儿童医院,
>2100份来自患有肺动脉高压(PAH,WHO I组)和正常儿童和成人的样本
成人和儿童对照,使用定制的多重ELISA检测肝癌衍生生长因子(HDGF)a
肺血管生成蛋白与PH生存率和功能结局显著相关(6分钟
步行距离),10和历史PH生物标志物作为基准,包括标准临床心力衰竭
生物标志物(NTproBNP、ST 2、GAL 3)、炎症(IL 6)和血管生成(VEGF和内皮抑制素)。内皮抑素
是特别重要的,因为它是胶原18 A的血管生成抑制剂片段,
与位于染色体21.11上的PH患者的生存和功能结局有关。
在母研究中,它只关注WHO I组肺动脉高压,不包括
唐氏综合症患者因此,考虑到PH在唐氏综合征中的发生率以及
在生物标志物研究中,迫切需要鉴定PH诊断/预后生物标志物,以改善
唐氏综合症的结果。
总体目的:加强“HDGF在肺动脉高压中的临床和机制作用”研究
使用组件2的INCLUDE研究目标,增加一个新的唐氏综合征队列,
有和没有PH的PH生物标志物分析以及与大型WHO第一组队列(N=2100)和正常队列的比较
成人(N=110)和儿童(N=165)。
英文摘要
Pulmonary hypertension (PH) in children or adults is a progressive and fatal disease characterized by sustained
elevations of pulmonary artery pressure of unknown etiology. Although the number of vasodilator drugs has
increased, still 20-30% of patients do not respond and non-responders have a poor prognosis eventually
requiring lung transplantation1-4. Pulmonary hypertension is frequently identified in patients with Down syndrome
and is associated with increased mortality, especially in patients with congenital heart disease (CHD).5-8 In the
University of Colorado Down syndrome clinic, 27.6% of patients had pulmonary hypertension.9 Although
pulmonary hypertension increases morbidity and mortality in subjects with Down syndrome, the underlying
disease burden and the role of specific comorbidities that increase the risk of developing pulmonary hypertension
in Down syndrome are not completely understood.9 A major reason, is we lack simple, minimally invasive more
lung/vascular specific, objective, repeatable, generalizable and less expensive measures of PH in Down
syndrome to improve outcomes. The study, “Clinical and mechanistic role of HDGF in pulmonary hypertension”
R01HL135114-02 awarded from the National Heart Lung and Blood Institute, aims to elucidate the in vitro and
in vivo mechanistic role of HDGF in Group I pulmonary artery hypertension and potential as a circulating
new measure of PAH severity, therapeutic response and survival.
With the parent study we have established collaborations with the NHLBI PAHBiobank at the University
of Cinicinnati, Vanderbilt University and Denver Children’s at the University of Colorado, and have assayed
>2100 samples from children and adults with pulmonary arterial hypertension (PAH, WHO Group I) and normal
adult and pediatric controls, using custom built multiplex ELISAs for hepatoma derived growth factor (HDGF) a
pulmonary angiogenic protein that is significantly associated with PH survival and functional outcomes (6 minute
walk distance),10 and historical PH biomarkers as benchmarks including the standard clinical heart failure
biomarkers (NTproBNP, ST2, GAL3), inflammation (IL6), and angiogenesis (VEGF and endostatin). Endostatin
is particularly important as it is an angiogenic inhibitor fragment of collagen 18A, and significantly associated
with survival and functional outcomes in patients with PH and located on Chromosome 21.11 Despite the success
of the parent study, it is focused only on WHO Group I pulmonary arterial hypertension and did not include
patients with Down syndrome. Therefore, considering the incidence of PH in Down syndrome and the paucity
of biomarker studies, there is an urgent need to identify PH diagnostic/prognostic biomarkers to improve
outcomes in Down syndrome.
Overarching objective: To augment the “Clinical and mechanistic role of HDGF in pulmonary hypertension” study
using the INCLUDE research objective of Component 2 to add a new Down Syndrome cohort for circulating
PH biomarker analysis with and without PH and comparison to a large WHO Group I cohort (N=2100) and normal
adults (N=110) and children (N=165).
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