Pharmacogenomics in Pulmonary Arterial Hypertension

肺动脉高压的药物基因组学

基本信息

批准号：
7252454
负责人：
RAYMOND Louis Benza
金额：
$ 44.56万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-01 至 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7252454
关键词：
Angiotensin II BMPR2 gene Clinic Clinical Clinical Research Clinical Trials Condition Development Disease Disease Progression Drug Interactions Elevation End Point Endothelial Cells Endothelin A Receptor Endothelin Receptor Endothelin-1 Enrollment Environment Epoprostenol Epoprostenol Receptors Family Fibrosis Genes Genetic Genetic Polymorphism Goals Histopathology Hypertrophy Individual Lesion Lung MADH4 gene Medial Metabolism Mutation New Agents Nitric Oxide Numbers Pathologic Patients Peptides Pharmaceutical Preparations Pharmacogenomics Population Prognostic Factor Prostacyclin synthase Prostaglandins I Proteins Protocols documentation Pulmonary Hypertension Pulmonary artery structure Pulmonary vessels Role Secondary to Serotonin Severities Severity of illness Smooth Muscle Myocytes Sum TBC 11251 Testing Thromboxanes Toxic effect Transforming Growth Factor beta Treprostinil Variant Vascular Endothelial Growth Factors Vascular resistance Vasodilator Agents analog base beraprost bosentan clinical efficacy cohort hemodynamics inhibitor/antagonist novel outcome forecast pressure primary pulmonary hypertension prospective pulmonary arterial hypertension response serotonin transporter vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Our goal is to determine clinically in PAH patients if associations exist between the efficacy and toxicity of sitaxsentan and bosentan and several gene polymorphisms in several key disease-specific and therapy specific genes. We will also characterize the relationship between these polymorphisms and PAH severity using either baseline hemodynamic or clinical surrogates for disease severity. Hypothesis: Polymorphisms influence the efficacy and toxicity of specific PAH therapy as well as development/severity of PAH via, their effect on PA remodeling, drug response or metabolism. This proposal will make use of a large population of well defined patients with PAH who were enrolled in several large clinical trials including Encysive protocols FPH02, 02x, 03 and 06 and a prospective cohort from four large PAH Centers. The sum total number of patients will be approximately 920, including 550 with PPH. This worldwide effort constitutes the largest clinical study of this deadly disease and in as such has great potential to alter clinical practice by revealing novel gene-drug interactions. We will test this hypothesis by executing the following Aims: Aim 1: Determine in PPH the relationship between known disease-specific polymorphisms (Serotorin transporter gene and PAI Hindlll) and variants in BMPR2 and SMAD4 with several well defined clinical efficacy endpoints of sitaxsentan and bosentan therapy. Aim 2: Determine in PAH the relationship between existing potentially "therapy-specific" polymorphism in the ET-1, ETAR, ETBR, NPR-c, prostacyclin receptor and prostacyclin synthase genes with several defined clinical efficacy endpoints of sitaxsentan and bosentan therapy. PAH = pulmonary arterial hypertension PA = pulmonary artery PPH = primary pulmonary hypertension

描述（由申请人提供）：如果Sitaxsentan和Bosentan的功效和毒性之间存在关联，以及在几个关键疾病特异性和治疗基因中的几种基因多态性，我们的目标是在PAH患者的临床上确定临床。我们还将使用基线血液动力学或临床替代物来表征这些多态性与PAH严重程度之间的关系。假设：多态性影响特定PAH治疗的功效和毒性以及PAH的发育/严重程度，它们对PA重塑，药物反应或代谢的影响。该提案将利用大量有明确的PAH患者的人群，这些患者已参加了几项大型临床试验，包括fph02、02X，03和06的常规方案，以及来自四个大PAH中心的前瞻性队列。患者的总数约为920，其中包括PPH的550。这项全球努力构成了这种致命疾病的最大临床研究，因此，通过揭示新的基因 - 药物相互作用来改变临床实践的巨大潜力。我们将通过执行以下目的来检验这一假设：目标1：确定BMPR2和SMAD4中已知疾病特异性多态性（5-羟色胺转运蛋白转运蛋白基因和PAI Hindlll）之间的关系与几个定义明确的临床效果端点和SMAD4中的变体之间的关系治疗。 AIM 2：在PAH中确定ET-1，ETAR，ETBR，NPR-C，Prostacyclin受体和前列环素合酶基因的现有潜在“特异性”多态性与几个定义的sitaxsentan和Bosentan疗法的临床效果之间的关系。 PAH =肺动脉高压 PA =肺动脉 PPH =原发性肺动脉高压