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通过我们题为“用于治疗肝纤维化的 C/EBP¿ 肽”的项目来解决。该提案的具体目标是：A) 合成与 Ac-KAVD-CHO 相关的肽，提高稳定性、细胞渗透性和生物利用度。这些肽旨在产生治疗人类肝纤维化的有效药物。 B) 在培养的原代活化人肝星状细胞中通过细胞凋亡测定筛选肽。将选择诱导靶细胞凋亡的肽。 C) 在培养的原代活化人肝星状细胞和无细胞系统中用 caspase 8 活化测定筛选肽。 D) 在小鼠模型中通过急性肝损伤/纤维发生测定筛选肽。 E) 通过毒理学[基因组；蛋白质组学；和代谢组学]在高度分化的原代人肝细胞中进行测定。 F) 在小鼠模型[持续损伤]中通过慢性肝纤维化测定筛选肽。在无细胞系统中使用核糖体 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，该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。该提案完成后，选定的化合物将准备好进行 RAID 提案，以完成 FDA 的 1 期研究。随后，将提交STTR提案，在大约3年内对慢性肝病患者进行FDA 2期临床研究。与《康复法案》的目标一致，保留我们研究小组（N = 3）、兽医医疗单位（N = 2；通过每日津贴）和退伍军人医学研究基金会（N = 2；通过间接费用）的研究人员将对这 7 个人及其家庭的财务状况产生积极影响。此外，该提案的成功完成将导致小型企业的创建（在加州大学圣地亚哥分校的保护下），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中疤痕组织的发展；这称为肝纤维化。 公众健康相关性：过度的肝纤维化可导致肝硬化，这是慢性肝病患者出现严重并发症和死亡的原因。肝硬化给美国带来的医疗和经济负担是巨大的，因为它与乙型和丙型肝炎、肥胖脂肪肝、糖尿病和酗酒有关。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有助于未来肺纤维化和肾纤维化的治疗。

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.