Clinical and mechanistic role of HDGF in pulmonary hypertension

HDGF 在肺动脉高压中的临床和机制作用

• 批准号: 9772631
• 负责人: ALLEN D EVERETT
• 金额: $ 27.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9772631
• 关键词: Activities of Daily Living; Address; Administrative Supplement; Adult; Affect; Age; Angiogenesis Inhibitors; Angiogenic Proteins; Award; BMPR2 gene; Benchmarking; Biological Assay; Biological Markers; Blood Vessels; CAV1 gene; Cell Line; Cell Proliferation; Cells; Child; Childhood; Chromosomes, Human, Pair 21; Clinic; Clinical; Clinical Research; Collaborations; Collagen; Colorado; Comorbidity; Custom; Data; Defect; Development; Diagnostic; Disease; Down Syndrome; Echocardiography; Endostatins; Etiology; Event; Funding; Future; Genes; Genomics; Goals; Harvest; Heart failure; Human; IL6 gene; In Vitro; Incidence; Inflammation; Link; Lung; Measures; Mediating; Mitogens; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Outcome; Parents; Pathway interactions; Patients; Pattern; Phenotype; Phosphorylation; Prognostic Marker; Proteomics; Pulmonary Hypertension; Pulmonary artery structure; Research; Risk; Role; Sampling; Sensitivity and Specificity; Serum; Severities; Signal Pathway; Smooth Muscle; Smooth Muscle Myocytes; Stimulation of Cell Proliferation; Systemic disease; Testing; Universities; Validation; Vascular Endothelial Growth Factors; Vasodilator Agents; Walking; angiogenesis; biobank; biomarker panel; burden of illness; circulating biomarkers; clinical practice; cohort; congenital heart disorder; defined contribution; experimental study; factor A; functional outcomes; genetic variant; hemodynamics; hepatoma-derived growth factor; improved outcome; in vivo; innovation; insight; minimally invasive; mortality; mutant; new therapeutic target; novel therapeutics; outcome forecast; pressure; prognostic; pulmonary arterial hypertension; response; success; survival outcome; survival prediction; therapeutic target; treatment response; vasculogenesis

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).

儿童或成人肺动脉高压（PH）是一种进行性致命性疾病，其特征是持续 病因不明的肺动脉压升高。尽管血管扩张药物的数量已 增加，但仍有 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。唐氏综合症患者经常发现肺动脉高压 并且与死亡率增加相关，尤其是患有先天性心脏病 (CHD) 的患者。5-8 科罗拉多大学唐氏综合症诊所显示，27.6% 的患者患有肺动脉高压。 9 尽管 肺动脉高压会增加唐氏综合症患者的发病率和死亡率，这是唐氏综合症的根本原因 疾病负担以及增加肺动脉高压风险的特定合并症的作用 9 一个主要原因，是我们缺乏简单、微创的更多方法 肺/血管特异性、客观、可重复、可推广且成本较低的唐氏 PH 测量方法 综合征以改善结果。该研究“HDGF 在肺动脉高压中的临床和机制作用” R01HL135114-02 由国家心肺和血液研究所授予，旨在阐明体外和血液 HDGF 在 I 类肺动脉高压中的体内机制作用及其作为循环药物的潜力 评估 PAH 严重程度、治疗反应和生存率的新方法。 通过母研究，我们与大学 NHLBI PAHBiobank 建立了合作 辛辛那提大学、范德比尔特大学和科罗拉多大学丹佛儿童医院，并进行了分析 >2100 个来自肺动脉高压（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) 肺血管生成蛋白与 PH 存活和功能结果显着相关（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、ST2、GAL3）、炎症（IL6）和血管生成（VEGF 和内皮抑素）。内皮抑素 特别重要，因为它是胶原蛋白 18A 的血管生成抑制剂片段，并且与 尽管取得了成功，但位于染色体 21.11 的 PH 患者的生存和功能结果 在母研究中，它仅关注 WHO I 组肺动脉高压，不包括 唐氏综合症患者。因此，考虑到唐氏综合症中 PH 的发生率和缺乏 在生物标志物研究中，迫切需要确定 PH 诊断/预后生物标志物以改善 唐氏综合症的结果。 总体目标：加强“HDGF 在肺动脉高压中的临床和机制作用”研究 使用第 2 部分的“包括”研究目标添加一个新的唐氏综合症队列以进行循环 有或没有 PH 的 PH 生物标志物分析以及与大型 WHO I 组队列 (N=2100) 和正常人的比较 成人 (N=110) 和儿童 (N=165)。