权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

A New Therapy for Bowel Ischemia-Reperfusion Injury

肠道缺血再灌注损伤的新疗法

基本信息

批准号：
7232761
负责人：
RONGQIAN WU
金额：
$ 13.91万
依托单位：
THERASOURCE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7232761
关键词：
Abdomen Acute Adult Amino Acids Animals Attenuated Binding Proteins Blood Blood flow Body Weight Bolus Infusion Cardiac Output Cardiovascular Physiology Cessation of life Clinical Trials Condition Continuous Infusion Creatinine Development Disulfides Dose Drug Kinetics Emergency Situation Enzymes Event Functional disorder Future Goals HMGB1 Protein Heart Human Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Injury Interleukin-1 alpha Interleukin-6 Intestines Ischemia Ischemic Bowel Disease Kidney Label Lead Liver Lung Marketing Measures Mesenteric Arteries Mesentery Modality Modeling Monitor Necrosis Normal saline Organ Outcome Patients Peptides Performance Perfusion Peripheral Resistance Peroxidase Phase Physiological reperfusion Radioactive Rat Protein Rate Rattus Reperfusion Injury Reperfusion Therapy Research Personnel Resuscitation Series Serum Shock Small Business Funding Mechanisms Small Business Innovation Research Grant Small Intestines Staining method Stains Structure Therapeutic Agents Time Tissue Sample Tissues Water adrenomedullin artery occlusion clinically relevant commercialization cytokine day dosage human adrenomedullin-binding protein 1 immunogenicity improved male mortality novel novel therapeutics preclinical study prevent programs response

项目摘要

DESCRIPTION (provided by applicant): Acute mesenteric ischemia is an abdominal emergency with a mortality rate of up to 60-80%. Even though numerous modalities and substances have been studied to reduce gut ischemia/reperfusion (I/R)-induced mortality, none have been entirely successful. As such, the development of effective strategies for preventing and treating circulatory collapse and organ injury after gut I/R is critical for the improvement of patient outcome under such conditions. The market potential for gut I/R treatment is estimated at $2-5 billion per year in the U.S. alone. We have recently demonstrated that administration of rat adrenomedullin (AM), a recently-discovered potent vasodilatory peptide, in combination with its novel specific binding protein (i.e., AMBP-1), at the beginning of reperfusion attenuated tissue injury and inflammatory responses in a rat model of gut I/R induced by superior mesenteric artery occlusion (SMAO). One obstacle hampering development of AM/AMBP-1 as a therapeutic agent for gut I/R is the potential immunogenicity of rat proteins in humans. Although we have shown that administration of rat AM plus human AMBP-1 at the beginning of reperfusion is protective, it remains unknown whether a combination of human AM and human AMBP-1 is also beneficial and, if so, whether delayed administration of AM/AMBP-1 (which is more clinically relevant) reduces gut I/R-induced mortality. We therefore hypothesize that administration of human AM/AMBP-1, even after reperfusion, improves cardiovascular function, attenuates organ injury and inflammation responses, and reduces mortality following gut I/R injury. The primary aim of this project is targeted toward demonstrating the feasibility of further development and commercialization of human AM/AMBP-1 as a novel resuscitation approach in reducing mortality after gut I/R. The optimal dosage(s) of human AM/AMBP-1 will be determined by assessing 1) the effect of a dose-response of AM/AMBP-1 on cardiovascular function, tissue injury and inflammatory responses after gut I/R; 2) the effect of a dose-response of AM/AMBP-1 on gut I/R-induced mortality; and 3) the pharmacokinetics of AM and AMBP-1 in normal animals and after gut I/R. Our ultimate goal (SBIR Phase II and beyond) is to obtain commercial utilization of human AM/AMBP-1 as a safe and effective treatment for patients with gut I/R injury.

描述（由申请人提供）：急性肠系膜缺血是一种腹部急症，死亡率高达 60-80%。尽管已经研究了多种方法和物质来降低肠道缺血/再灌注 (I/R) 引起的死亡率，但没有一种方法和物质完全成功。因此，制定预防和治疗肠道缺血再灌注后循环衰竭和器官损伤的有效策略对于改善此类情况下的患者预后至关重要。据估计，仅在美国，肠道 I/R 治疗的市场潜力每年就达 2-50 亿美元。我们最近证明，在肠系膜上动脉闭塞（SMAO）诱导的肠道 I/R 大鼠模型中，在再灌注开始时给予大鼠肾上腺髓质素（AM）（一种最近发现的强效血管舒张肽）与其新型特异性结合蛋白（即 AMBP-1）相结合，可减轻组织损伤和炎症反应。阻碍 AM/AMBP-1 作为肠道 I/R 治疗剂开发的一个障碍是大鼠蛋白在人类中的潜在免疫原性。尽管我们已经证明在再灌注开始时给予大鼠 AM 加人 AMBP-1 具有保护作用，但仍不清楚人 AM 和人 AMBP-1 的组合是否也有益，如果是的话，延迟给予 AM/AMBP-1（临床上更相关）是否会降低肠道 I/R 诱导的死亡率。因此，我们假设施用人 AM/AMBP-1，即使在再灌注后，也能改善心血管功能，减轻器官损伤和炎症反应，并降低肠道 I/R 损伤后的死亡率。该项目的主要目的是证明人类 AM/AMBP-1 作为一种降低肠道缺血再灌注后死亡率的新型复苏方法的进一步开发和商业化的可行性。人AM/AMBP-1的最佳剂量将通过以下评估来确定：1)AM/AMBP-1的剂量反应对肠道I/R后心血管功能、组织损伤和炎症反应的影响； 2) AM/AMBP-1的剂量反应对肠道I/R诱导的死亡率的影响； 3) AM 和 AMBP-1 在正常动物和肠道 I/R 后的药代动力学。我们的最终目标（SBIR II 期及以后）是获得人类 AM/AMBP-1 的商业利用，作为肠道 I/R 损伤患者的安全有效的治疗方法。