Novel peptide to inhibit burn injury progression

抑制烧伤进展的新型肽

• 批准号: 7941017
• 负责人: RICHARD August CLARK
• 金额: $ 84.21万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941017
• 关键词: Accident and Emergency department; Address; Adult; Amino Acids; Animals; Apoptosis; Apoptotic; Blood Vessels; Burn Centers; Burn injury; Cell Culture System; Cell Death; Cells; Cessation of life; Cicatrix; Clinical Trials; Comb animal structure; Contracts; DNA Modification Process; Data; Dermal; Direct Costs; Dose; Economic Burden; Endothelial Cells; Equilibrium; Excision; Expenditure; Facilities and Administrative Costs; Family suidae; Fibroblasts; Fibronectins; Funding; Granulation Tissue; HMGB1 Protein; Hospitalization; Human; Image; In Situ Nick-End Labeling; In Vitro; Infection; Infusion procedures; Injury; Lasers; Lipid Peroxidation; Location; MAPK8 gene; Measures; Messenger RNA; Modeling; Monitor; Necrosis; Normal tissue morphology; Nuclear; Outcome; Pain; Patient Care; Patients; Peptides; Phase; Principal Investigator; Protein Array; Proteins; Proteome; Rattus; Reporting; Skin; Specimen; Stress; Time Study; Tissues; Toxicokinetics; Treatment Protocols; Video Microscopy; Visual; Western Blotting; base; caspase-3; cost; cytokine; design; in vivo; keratinocyte; morphometry; mortality; novel; oxidation; prevent; programs; research study; response; social; tissue culture

DESCRIPTION (provided by applicant): Burns are one of the most common and devastating injuries known to mankind. Each year in the US approximately 500,000 patients with burns present to emergency departments. Of 40,000 annual hospitalizations, 25,000 burn victims are admitted to specialized burn centers annually. The overall mortality from burns is around 5%, with nearly 4000 deaths reported yearly. In addition, the human, social and economic burden of burns is considerable with an estimated annual expenditure of more than $2 billion direct costs and much greater indirect costs. Funding of this proposal would be a step toward fulfilling an unmet need in the care of patients with severe burns, i.e. treatment to prevent burn injury progression. Such therapy would potentially reduce pain and suffering, minimize need for excision and grafting, decrease infection rate, reduce hospitalization, diminish cost and lessen scarring of burn victims. Proof of principle for such a therapy has been obtained with a fibronectin-derived 14 amino acid peptide (P12) administered intravenously 1 and 24 hr after burn injury in a rat hot comb model. Almost complete inhibition of burn injury progression was achieved in this model with optimal doses of P12. Large animal confirmation of this finding is required prior to the initiation of clinical trials with this novel therapy. Therefore, we propose to confirm the rat studies and optimize the treatment protocol in a validated porcine hot comb model (AIM 1). Porcine models are generally recognized as best for studying injuries to human skin since porcine skin most closely resembles that of humans. In addition, we propose in vivo and in vitro studies to better elucidate P12 mechanism of action (AIMs 2 and 3, respectively). Based on preliminary results with adult human dermal fibroblasts (AHDF), we hypothesize that P12 protects cells from apoptotic or necrotic death induced by oxidative and cytokine stress. In vivo studies to address this hypothesis (AIM 2) will be performed on tissue specimens from the porcine experiments outlined in AIM 1; however, the in vitro studies will utilize human skin cells to bridge the gap from other animal species to human. Results from AIMs 1 - 3 and P12 stability and toxicokinetic studies from AIM 4 are critical for the design of Phase I and II clinical trials (AIM 4). PHS 398/2590 (Rev. 11/07) Page 1 Continuation Format Page

描述（由申请人提供）：烧伤是人类已知的最常见和最具破坏性的伤害之一。在美国，每年约有50万名烧伤患者到急诊室就诊。在每年住院的4万人中，每年有2.5万名烧伤患者被送入专门的烧伤中心。烧伤的总死亡率约为5%，每年有近4000人死亡。此外，烧伤造成的人类、社会和经济负担相当沉重，估计每年的直接费用超过20亿美元，间接费用则大得多。为该提案提供资金将是朝着满足严重烧伤患者护理方面未满足的需求迈出的一步，即通过治疗预防烧伤进展。这种疗法可能会减少疼痛和痛苦，最大限度地减少切除和移植的需要，降低感染率，减少住院治疗，降低成本并减少烧伤患者的疤痕。在大鼠热梳模型中，在烧伤后1和24小时静脉给予纤维连接蛋白衍生的14个氨基酸肽（P12），获得了这种治疗的原理证明。在该模型中，最佳剂量的P12几乎完全抑制了烧伤的进展。在这种新疗法的临床试验开始之前，需要在大型动物身上证实这一发现。因此，我们建议在猪热梳模型（AIM 1）中验证大鼠研究并优化治疗方案。猪模型通常被认为是研究人类皮肤损伤的最佳模型，因为猪皮肤与人类皮肤最相似。此外，我们提出了体内和体外研究来更好地阐明P12的作用机制（AIMs 2和AIMs 3）。基于成人真皮成纤维细胞（AHDF）的初步结果，我们假设P12可以保护细胞免受氧化应激和细胞因子应激诱导的凋亡或坏死死亡。为解决这一假设（AIM 2）的体内研究将在AIM 1中概述的猪实验的组织标本上进行；然而，体外研究将利用人类皮肤细胞来弥合从其他动物物种到人类的差距。AIMs 1 - 3和P12的稳定性和毒性动力学研究结果对I期和II期临床试验（AIM 4）的设计至关重要。PHS 398/2590 （Rev. 11/07）第1页延续格式页