PAI-1 Targeted Intrapleural Fibronolytic Therapy

PAI-1靶向胸膜内纤溶治疗

• 批准号: 8259726
• 负责人: Steven Idell
• 金额: $ 42.48万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259726
• 关键词: Address; Alteplase; Biological Availability; Cicatrix; Clinical; Clinical Trials; Collection; Data; Deposition; Development; Disease; Docking; Dose; Drainage procedure; Empyema; Enzyme Precursors; Europe; Fibrin; Funding; Goals; Human; Injury; Intervention; Liquid substance; Lung; Medical; Mesothelial Cell; Modeling; Molecular Conformation; Molecular Target; Monoclonal Antibodies; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Plasma; Plasmin; Plasminogen Activator Inhibitor 1; Pleural; Pre-Clinical Model; Production; Publishing; Refractory; Research Personnel; Safety; Serpins; Testing; Tetracyclines; Therapeutic; Therapeutic Clinical Trial; Thrombolytic Therapy; Tissues; Toxicology; Treatment Efficacy; Treatment outcome; United States National Institutes of Health; Urokinase; Work; efficacy testing; effusion; improved; in vivo; innovation; meetings; multidisciplinary; novel; novel strategies; response; therapeutic target; treatment strategy; urokinase inhibitor

DESCRIPTION (provided by applicant): Pleural drainage is required for complicated parapneumonic effusions and empyema in up to 40,000 US patients annually. Intrapleural fibrinolytic therapy (IPFT), which enhances clearance of pleural loculation to augment pleural drainage, remains a therapeutic option that obviates the need for surgical drainage. However, current IPFT is limited by variable efficacy, uncertain dosing and safety concerns that are underscored by ttie disparate results of recent clinical trials. These are important clinical problems that mandate the search for better IPFT. Plasminogen activator inhibitor-1 (PAI-1) is strongly implicated in the pathogenesis of pleural loculation and inhibits tissue and urokinase plasminogen activators; tPA and uPA, which are currently used for IPFT. Our hypothesis that intrapleural neutralization of PAI-1 will further improve IPFT is strongly supported by published work and preliminary data. Our objective is to improve outcomes of treatment for organizing pleural injury using novel PAI-1-targeted interventions. The Specific Aims are: 1) To determine if molecules that compete with fibrinolysins for PAI-1 enhance the ability of fibrinolysins (tPA or single chain urokinase) to clear pleural loculations. 2) To detennine if mAbs that potentiate inactivation of PAI-1 via latency or substrate pathway redirection increase the therapeutic potential of fibrinolysins. 3) To test the ability of PAI-1 targeted interventions to potentiate profibrinolytic responses of human and rabbit primary mesothelial cells and in human pleural fluids. We will also test the efficacy of PAI-1 targeted interventions in rabbit models of empyema and tetracycline- induced pleural injury enhanced with adenoviral delivery of human PAI-1. Our approach is innovative as intrapleural targeting of PAI-1 has never before been evaluated. We will meet milestones that can be accomplished by our multidisciplinary team within the two year funding period. At the end of this project, we will identify a prime interventional PAI-1 -targeted candidate and one or two backups. We will develop the most effective novel PAI-1- targeted therapeutics in CADET II for clinical trial testing. This project addresses a key gap in medical practice and could advance the field of IPFT through identification of more reliable, more effective and potentially safer treatment strategies for patients with pleural loculation. RELEVANCE (See instructionsV Intrapleural fibrinolytic therapy (IPFT) is often used as a less invasive alternative to surgery to treat patients with pleural loculation (scarring and fluid collections), but its efficacy remains controversial. We infer that outcomes of IPFT will be improved by PAI-1-targeting, a novel approach that addresses a critical mechanism of pleural injury. Ultimately, new interventions identified in this project could improve outcomes for thousands of afflicted US patients annually.

描述（由申请人提供）：每年多达40,000名美国患者中，复杂的脑py虫积液和脓肿需要胸膜引流。胸膜内纤维蛋白水解疗法（IPFT）增强了胸膜切割以增加胸膜引流的清除，它仍然是一种治疗选择，可以消除对手术引流的需求。但是，当前的IPFT受到可变疗效，不确定的给药和安全问题的限制，这些问题受到最近临床试验的不同结果的强调。这些是重要的临床问题，可以要求寻找更好的IPFT。纤溶酶原激活剂抑制剂1（PAI-1）与胸膜定位的发病机理非常重要，并抑制组织和尿激酶纤溶酶原激活剂。 TPA和UPA，目前用于IPFT。我们的假设是，PAI-1的胸膜内中和将进一步改善IPFT，这得到了公开的工作和初步数据的强烈支持。我们的目标是通过新型PAI-1靶向干预措施改善组织胸膜损伤的治疗结果。具体目的是：1）确定与纤维纤维蛋白竞争PAI-1的分子是否增强了纤维纤维蛋白（TPA或单链尿激酶）清除胸膜胸膜位置的能力。 2）确定是否通过潜伏期或底物途径重定向PAI-1灭活的mAb增加了纤维纤维蛋白的治疗潜力。 3）测试PAI-1靶向干预措施增强人和兔子原代间皮细胞以及人胸膜液中的纤维蛋白水解反应的能力。我们还将测试PAI-1靶向干预措施在脓肿模型和四环素诱导的胸膜损伤中的疗效，随着人PAI-1的腺病毒递送增强了胸膜损伤。我们的方法具有创新性，因为PAI-1的胸腔内靶向从未被评估过。我们将遇到在两年资金期内我们的多学科团队可以完成的里程碑。在该项目结束时，我们将确定一个由PAI -1型候选者和一个或两个备份的主要介入。我们将在Cadet II中开发最有效的新型PAI-1靶向治疗剂进行临床试验测试。该项目解决了医学实践中的关键差距，并可以通过确定为胸膜局部局部的患者确定更可靠，更有效，更安全的治疗策略来推动IPFT领域。 RELEVANCE (See instructionsV Intrapleural fibrinolytic therapy (IPFT) is often used as a less invasive alternative to surgery to treat patients with pleural loculation (scarring and fluid collections), but its efficacy remains controversial. We infer that outcomes of IPFT will be improved by PAI-1-targeting, a novel approach that addresses a critical mechanism of pleural injury. Ultimately, new interventions identified in this project could每年饱受折磨的美国患者的预后改善。

项目成果

Remarkable stabilization of plasminogen activator inhibitor 1 in a "molecular sandwich" complex.

• DOI: 10.1021/bi400470s
• 发表时间: 2013-07-09
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Florova, Galina;Karandashova, Sophia;Declerck, Paul J.;Idell, Steven;Komissarov, Andrey A.
• 通讯作者: Komissarov, Andrey A.

The time course of resolution of adhesions during fibrinolytic therapy in tetracycline-induced pleural injury in rabbits.

兔四环素引起的胸膜损伤纤溶治疗期间粘连消退的时间过程。

• DOI: 10.1152/ajplung.00136.2015
• 发表时间: 2015
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Komissarov,AndreyA;Florova,Galina;Azghani,AliO;Buchanan,Ann;Bradley,WilliamM;Schaefer,Chris;Koenig,Kathleen;Idell,Steven
• 通讯作者: Idell,Steven