C/EBP beta Peptides for the Treatment of Hepatic Fibrosis

描述（由申请人提供）：主题（AA-101）肝纤维化药物开发将在我们题为“C/EBP肽治疗肝纤维化”的项目中讨论。A）合成与Ac-KAVD-CHO相关的具有改善的稳定性、细胞渗透性和生物利用度的肽。这些肽被设计用于产生用于人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测定筛选肽。将选择诱导靶细胞凋亡的肽。C）在培养的原代活化的人肝星状细胞和无细胞系统中用半胱天冬酶8活化测定筛选肽。D）在小鼠模型中用急性肝损伤/纤维化发生测定筛选肽。E）在高度分化的原代人肝细胞中用毒理学[基因组学;蛋白质组学;和代谢组学]测定筛选肽。F）在小鼠模型[具有持续损伤]中用慢性肝纤维化测定筛选肽。在无细胞系统中用核糖体S-6激酶测定筛选肽。G）在无细胞系统中用多激酶测定筛选肽。有令人信服的证据表明，拟议的研究将产生一种治疗肝纤维化的药物，至少与先导肽一样有效和安全，但具有改善的生物利用度，稳定性和/或细胞渗透性。在完成本提案后，选定的化合物将准备好RAID提案，以完成FDA 1期研究。随后，将提交STTR提案，在大约3年内对慢性肝脏疾病患者进行FDA 2期临床研究。与恢复法的目的一致，保留研究人员在我们的研究小组（N=3），在兽医医疗单位（N=2;通过每日津贴），并在退伍军人医学研究基金会（N=2;通过间接费用）将有一个积极的影响，在这7个人及其家庭的财务状况。此外，该提案的成功完成将导致创建一个小企业（在加州大学圣地亚哥分校的保护伞下），对美国经济产生额外影响慢性肝病，通过炎症和损伤诱导肝脏瘢痕组织的发展;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化，这是慢性肝病人群中显著的并发症和死亡率。肝硬化给美国带来的医疗和经济负担是巨大的，因为它与B和C型肝炎、肥胖脂肪肝、糖尿病和酒精中毒有关。通过这项工作获得的额外知识将促进治疗肝纤维化的药物的开发。肝纤维化的有效治疗方法的发展也可能促进肺和肾纤维化的未来治疗。

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.