Refanalin for lung preservation and transplantation

Refanalin 用于肺保存和移植

• 批准号: 7273432
• 负责人: WEIZHONG CAI
• 金额: $ 25.45万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7273432
• 关键词: 3-Dimensional; Animal Model; Animals; Apoptosis; Apoptotic; Attenuated; Biochemistry; Biological Assay; Biological Preservation; Biology; Blood Vessels; Blood gas; Cell Death; Cell Survival; Cells; Clinical; Complication; Cryopreservation; Cystic Fibrosis; DNA Nucleotidylexotransferase; Daily; Data; Development; Dextrans; Diffuse; Endothelial Cells; Epithelial; Epithelial Cells; Factor Analysis; Freezing; Functional disorder; Glucose; Goals; Growth Factor; Half-Life; Hamman-Rich syndrome; Harvest; Hepatocyte Growth Factor; Hour; Human; In Vitro; Incidence; Injury; Ischemia; Kidney Transplantation; Label; Lead; Left lung; Liquid substance; Liver; Lung; Lung Transplantation; Lung diseases; Measurement; Measures; Modeling; Morbidity - disease rate; Mus; Necrosis; Nitrogen; Nuclear; Numbers; Organ; Organ Harvestings; Organ Preservation; Organ Transplantation; Oxygen; Patients; Perfusion; Phage Display; Pharmaceutical Preparations; Phase; Physiological reperfusion; Population; Potassium; Preservation Technique; Propidium Diiodide; Proteins; Pulmonary Emphysema; Range; Rate; Rattus; Recombinants; Reperfusion Injury; Reperfusion Therapy; Resort; Respiratory physiology; Rodent; Solutions; Staging; Staining method; Stains; Survival Rate; Techniques; Therapeutic; Time; Tissues; Transferase; Transplant Recipients; Transplantation; Trypan Blue; Umbilical vein; Work; cell injury; cell type; day; design; dextran; drug discovery; graft failure; improved; in vivo; lung injury; lung preservation; mimetics; molecular modeling; mortality; pre-clinical; prevent; protective effect; small molecule; success

DESCRIPTION (provided by applicant): Lung transplantation has become the mainstay of therapy for most end stage lung diseases including pulmonary emphysema, cystic fibrosis, and idiopathic pulmonary fibrosis. However, increasing demand for suitable donor lungs far exceeds the number of available organs, in part because the lung is exquisitely sensitive to ischemia. Mild to severe ischemia-reperfusion injury is a frequent complication in lung transplant recipients. Current preservation fluids (e.g., low-potassium dextran glucose, LPDG) reliably preserve harvested lungs for 4 to 8hr and do not exploit recent advances in understanding of apoptosis to minimize lung injury during preservation. Hepatocyte growth factor (HGF), also known as scatter factor (SF), is a pleiotropic growth factor that induces the activation and proliferation of diverse cell types, largely through its mitogenic and anti-apoptotic activities. Addition of recombinant SF/HGF to the preservation solution enhances post-transplant organ function. While administration of SF/HGF as protein therapy has potential for the treatment of lung dysfunction, its feasibility is limited by issues relating to inherent instability of proteins in solution and limited tissue half-life. Using a drug discovery engine that includes phage display, 3-dimensional molecular modeling, we have identified Refanalin, an organic small molecule SF/HGF mimetic that could serve as important therapeutics in ameliorating lung dysfunction and reducing early graft failure following transplantation. The objective of our study is to extend the lung preservation time up to 12-18 hr for lung transplantation using our lead SF/HGF mimetic as an additive to current preservation solutions. Preliminary data indicate that Refanalin protects against apoptotic/necrotic cell death in vitro and preserves organ function in vivo. In addition, Refanalin can improve success rate in liver and kidney transplantation in our animal models. The proposed work is designed to identify a strategy to determine the protective effects of Refanalin against ischemia-induced apoptosis/necrosis in lung transplantation in an animal model. Lung transplantation has become the mainstay of therapy for most end stage lung diseases including pulmonary emphysema, cystic fibrosis, and idiopathic pulmonary fibrosis. A small- molecule drug that increases the preservation time of donor lungs will have tremendous clinical benefits.

描述(申请人提供)：肺移植已成为大多数终末期肺部疾病的主要治疗方法，包括肺气肿、囊性纤维化和特发性肺纤维化。然而，对合适的供体肺的需求不断增加，远远超过了可用的器官数量，部分原因是肺对缺血非常敏感。轻度至重度缺血再灌注损伤是肺移植受者常见的并发症。目前的保存液(如低钾葡聚糖，LPDG)能够可靠地保存所采集的肺4至8小时，并且没有利用细胞凋亡的最新进展来最大限度地减少保存过程中的肺损伤。肝细胞生长因子(HGF)，又称散射因子(SF)，是一种多效性生长因子，主要通过其促有丝分裂和抗凋亡活性诱导多种细胞类型的激活和增殖。在保存液中加入重组SF/HGF可增强移植后器官功能。虽然应用SF/HGF作为蛋白质疗法具有治疗肺功能障碍的潜力，但其可行性受到与蛋白质在溶液中的固有不稳定性和有限的组织半衰期有关的问题的限制。利用包括噬菌体展示、三维分子建模在内的药物发现引擎，我们已经确定了Refanalyin，一种有机小分子SF/HGF模拟物，可能在改善肺功能障碍和减少移植后早期移植失败方面发挥重要的治疗作用。我们研究的目的是使用我们的先导SF/HGF模拟物作为当前保存液的添加剂，将肺移植的保存时间延长到12-18小时。初步数据表明，Refanalyin在体外可防止细胞凋亡/坏死，并在体内保护器官功能。此外，在我们的动物模型中，Refanalyin还可以提高肝和肾移植的成功率。这项拟议的工作旨在确定一种策略，以确定瑞法林对动物模型肺移植中缺血诱导的细胞凋亡/坏死的保护作用。肺移植已经成为包括肺气肿、囊性纤维化和特发性肺纤维化在内的大多数终末期肺部疾病的主要治疗手段。一种能延长供体肺保存时间的小分子药物将会带来巨大的临床益处。