C/EBP beta Peptides for the Treatment of Hepatic Fibrosis

描述(由申请人提供)：题目(AA-101)治疗肝纤维化的药物开发将与我们的项目“C/EBP？治疗肝纤维化的多肽”一起讨论。这项建议的具体目标是：a)合成与Ac-KAVD-CHO相关的多肽，具有更好的稳定性、细胞渗透性和生物利用度。这些多肽的设计是为了产生一种治疗人类肝纤维化的有效药物。B)在培养的原代活化的人肝星状细胞中用细胞凋亡试验筛选多肽。将选择诱导靶细胞凋亡的多肽。C)在原代激活的人肝星状细胞和无细胞系统中，用caspase 8激活试验筛选多肽。D)在小鼠模型中用急性肝损伤/肝纤维化试验筛选多肽。E)在高分化的原代人肝细胞中用毒理学[基因组；蛋白质组；和代谢组学]分析筛选多肽。F)在[持续损伤]的小鼠模型中用慢性肝纤维化试验筛选多肽。利用核糖体S-6蛋白在无细胞体系中筛选多肽。G)在无细胞系统中用多酶试验筛选多肽。有令人信服的证据表明，拟议的研究将导致一种治疗肝纤维化的药物，该药物至少与主肽一样有效和安全，但具有更好的生物利用度、稳定性和/或细胞渗透性。在这项建议完成后，选定的化合物将为完成FDA第一阶段研究的突击计划做好准备。随后，将提交一份STTR提案，在大约3年内对慢性肝病患者进行FDA第二阶段临床研究。根据《恢复法》的目标，在我们的研究组(N=3)、兽医医疗股(N=2；通过每日)和退伍军人医学研究基金会(N=2；通过间接费用)保留研究人员将对这7人及其家人的财务状况产生积极影响。此外，这项提案的成功完成将导致小企业(在加州大学圣地亚哥分校的保护伞下)的创建，以及对美国经济的额外影响，慢性肝病通过炎症和损伤诱导肝脏中疤痕组织的发展；这被称为肝纤维化。 公共卫生相关性：过度的肝纤维化可导致肝硬变，这是慢性肝病患者发生严重并发症和死亡的主要原因。肝硬变给美国带来了巨大的医疗和经济负担，因为它与乙肝和丙型肝炎、肥胖性脂肪肝、糖尿病和酒精中毒有关。通过这项工作获得的更多知识将有助于开发治疗肝纤维化的药物。开发有效的肝纤维化治疗方法也可能促进未来对肺和肾纤维化的治疗。

DESCRIPTION (provided by applicant): Topic (AA-101) Medication Development for Hepatic Fibrosis will be addressed with our project entitled "C/EBP¿ Peptides for the Treatment of Hepatic Fibrosis". The Specific Aims of this proposal are: A) Synthesis of peptides related to Ac-KAVD-CHO with improved stability, cell penetration and bioavailability. These peptides were designed to yield an effective medication for human hepatic fibrosis. B) Screening of peptides with an apoptosis assay in cultured primary activated human hepatic stellate cells. Peptides inducing apoptosis of the target cell will be selected. C) Screening of peptides with caspase 8 activation assays in cultured primary activated human hepatic stellate cells, and cell-free systems. D) Screening of peptides with an acute liver injury/fibrogenesis assay in mouse models. E) Screening of peptides with toxicological [genomic; proteomic; and metabolomic] assays in highly differentiated primary human hepatocytes. F) Screening of peptides with a chronic liver fibrosis assay in mouse models [with ongoing injury]. Screening of peptides with a ribosomal S-6 kinase assay in cell-free systems. G) Screening of peptides with a multi-kinase assay in cell-free systems. There is compelling evidence that the proposed research will result in a medication for hepatic fibrosis that is at least as effective and safe as the lead peptide but with improved bioavailability, stability and/or cell penetration. Upon completion of this proposal, the selected compound will be ready for a RAID proposal to complete FDA phase 1 studies. Subsequently, a STTR proposal will be submitted to perform FDA phase 2 clinical studies in patients with chronic liver diseases in approximately 3 years. In agreement with the aims of the Recovery Act, retaining research personnel in our research group (N=3), at the Veterinarian Medical Unit (N=2; through per diem), and at the Veterans Medical Research Foundation (N=2; through indirect costs) will have a positive impact in the financial situation of these 7 individuals and their families. Moreover, the successful completion of this proposal will lead to the creation of a Small Business (under the umbrella of the University of California, San Diego), with the additional impact in the US economy Chronic liver diseases, through inflammation and injury induce the development of scar tissue in the liver; this is called liver fibrosis. PUBLIC HEALTH RELEVANCE: Excessive liver fibrosis can result in liver cirrhosis, which accounts for the significant complications and mortality among the population with chronic liver diseases. The medical and financial burden of cirrhosis to the USA is substantial, as it is associated with Hepatitis B and C, fatty liver of obesity and diabetes and alcoholism. Additional knowledge gained by this work will facilitate the development of medication for the treatment of liver fibrosis. Development of effective treatments for liver fibrosis may also facilitate future treatments for lung and kidney fibrosis.