Targeting PI3K/BRD4 and Hedgehog Pathway in Alcohol Associated Liver Disease

靶向 PI3K/BRD4 和 Hedgehog 通路治疗酒精相关性肝病

基本信息

批准号：
10351877
负责人：
Virender Kumar
金额：
$ 10.56万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10351877
关键词：
AKT inhibition Acetaldehyde Alcohol abuse Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols Area Award Binding Biodistribution Blood CYP2E1 gene Cell Survival Cells Cessation of life Cirrhosis Cleaved cell Collaborations DNA Damage Data Deposition Development Diagnosis Diet Disease Disease Progression Disease regression Drug Delivery Systems Drug Kinetics Encapsulated Environment Erinaceidae Ethanol Extracellular Matrix Faculty Fatty Acids Fatty acid glycerol esters Fibroblasts Fibrosis Funding GLI Family Protein GLI gene Gene Family Genes Goals Grant HMGB1 Protein Hepatic Stellate Cell Hepatitis C Therapy Hepatocyte Human Hydrophobicity Immune response In Vitro Industry Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Knowledge Kupffer Cells Leadership Leaky Gut Ligands Lipid Peroxidation Lipids Lipopolysaccharides Liver Liver Fibrosis Liver diseases Malignant neoplasm of pancreas Mediating Mentors Morbidity - disease rate Mus NF-kappa B Nature Necrosis Oxides PI3K/AKT Pathogenesis Pathway interactions Patients Peptide Hydrolases Peptides Pharmaceutical Preparations Platelet-Derived Growth Factor Platelet-Derived Growth Factor beta Receptor Production Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins c-akt Public Health Pulmonary Inflammation Recombinants Research Research Personnel Role Sampling Scientist Signal Pathway Signal Transduction Students Surface TLR4 gene Training Transcription Coactivator Treatment Efficacy United States Up-Regulation Writing alcohol abstinence alcohol abuse therapy amphiphilicity base c-myc Genes career career development cell transformation chronic liver injury conventional therapy cytokine dietary control experience fibroblast-activating factor gene function in vivo inhibitor/antagonist innovation kidney fibrosis liver inflammation liver injury liver transplantation member nanocarrier nanomedicine nanoparticle new therapeutic target next generation novel novel therapeutics overexpression prevent protein expression response skills smoothened signaling pathway tenure track wound healing

项目摘要

PROJECT SUMMARY This K01 application aims to promote the applicant's development to become a multi-disciplinarily trained and independent academic researcher. This application's collective strengths are defined in these 3 major areas: 1) Credentials: PI's application builds upon his productive track-record to achieve scientific independence in the field of drug delivery and liver fibrosis, including alcohol-associated liver disease (AALD). The PI's goals include enhancing grantsmanship, leadership, and team management skills to become an independent, tenure-track academic researcher. In addition to technical training, PI intends to build skills in communicating with faculty members, industry members, and students. 2) Training Environment: Drs. Mahato (mentor) and Kharbanda, and Cheng (co-mentors) are world-class researchers and fully committed to advancing the PI's career. Particular emphasis will be given to grant writing, collaboration building, and applying for external funding. The mentoring committee has strong credentials in developing the next generation of successful academic scientists. The knowledge and experience gained during this award period will help the candidate generate data to apply for an R21/R01 grant. 3) Innovative Research: PI's central hypothesis is that alcohol-induced activation of inflammatory pathways is mediated by AKT and BRD4 and synergize with the hedgehog (Hh) pathway to promote AALD. Simultaneous inhibition of these pathways using targeted nanomedicine could alleviate the progression of AALD and related morbidities. The PI has generated the following preliminary results; (a) Conditioned media from the EtOH treated primary human hepatocytes significantly stimulated hepatic stellate cells (HSCs) as determined by α-SMA expression levels and upregulated GLI1/2 activity; (b) The protein cMYC is upregulated in patient samples diagnosed with alcoholic hepatitis; (c) Treatment with novel inhibitors MDB5 (Hh) and SF2523 (PI3K/BRD4) showed decreased their target genes in HSC-T6 cells; (d) EtOH diet-fed mice show increased p- AKT, cMYC, and GLI1/2 protein levels in the liver compared to mice on the control diet; (e) Treatment with MDB5 and SF2523 decreased liver injury markers ALT and AST, and lowered GLI1, cMYC, and p-AKT protein levels in ethanol-fed mice; (f) Novel cleavable amphiphilic peptide (CAP) was self-assembled into nanoparticles (NPs) of size range 100± 10 nm loaded with both the drugs (payload 5% w/w); (g) CAP-NPs were sensitive to fibroblast activation protein (FAP-α), and NPs dissembled in presence of recombinant FAP-α. Based on these robust results, the proposal has the following specific aims: Aim 1. Establish the role of AKT/BRD4 dual inhibitor SF2523 and Hh inhibitor MDB5 in AALD. Aim 2. Formulate and characterize HSC targeted CAP-NP loaded with SF2523 and MDB5. Aim 3. Determine therapeutic efficacy of SF2523 and MDB5 loaded pPB-CAP-NPs in ALD mice. The new knowledge and nanomedicine generated in this proposal may open new therapeutic avenues for the treatment of AALD.

项目概要本K01申请旨在促进申请人发展成为一名受过多学科培训和该应用程序的集体优势定义在以下 3 个主要领域：1) 证书：PI 的申请建立在他富有成效的记录之上，以实现该领域的科学独立性药物输送和肝纤维化领域，包括酒精相关性肝病 (AALD)。提高资助能力、领导力和团队管理技能，成为一名独立的终身教授除了技术培训之外，PI 还打算培养与教师沟通的技能。 2）培训环境：Mahato博士（导师）和Kharbanda，以及 Cheng（联合导师）是世界一流的研究人员，完全致力于推动 PI 的职业生涯。重点将放在资助写作、合作建设和申请外部资金上。委员会在培养下一代成功的学术科学家方面拥有强大的资质。在此奖励期间获得的知识和经验将帮助候选人生成数据以申请 R21/R01 资助 3) 创新研究：PI 的中心假设是酒精诱导炎症激活。途径由 AKT 和 BRD4 介导，并与刺猬 (Hh) 途径协同促进 AALD。使用靶向纳米药物同时抑制这些途径可以缓解 AALD 的进展 PI 产生了以下初步结果； EtOH 处理的原代人肝细胞显着刺激肝星状细胞 (HSC)，如下所示： α-SMA 表达水平和 GLI1/2 活性上调；(b) 患者体内蛋白质 cMYC 上调；诊断患有酒精性肝炎的样本；(c) 使用新型抑制剂 MDB5 (Hh) 和 SF2523 进行治疗 (PI3K/BRD4) 在 HSC-T6 细胞中显示出其靶基因减少；(d) 乙醇饮食喂养的小鼠显示出 p- 增加；与对照饮食的小鼠相比，肝脏中的 AKT、cMYC 和 GLI1/2 蛋白水平； MDB5 和 SF2523 降低肝损伤标志物 ALT 和 AST，并降低 GLI1、cMYC 和 p-AKT 蛋白（f）新型可裂解两亲肽（CAP）自组装成纳米颗粒 (NP)，尺寸范围为 100± 10 nm，负载两种药物（有效负载 5% w/w）；(g) CAP-NP 对成纤维细胞激活蛋白（FAP-α），以及在重组 FAP-α 存在下分解的 NP。结果稳健，该提案有以下具体目标：目标 1. 确立 AKT/BRD4 双重抑制剂的作用 AALD 中的 SF2523 和 Hh 抑制剂 MDB5 目标 2. 配制并表征 HSC 靶向负载的 CAP-NP。目标 3. 确定 SF2523 和 MDB5 负载的 pPB-CAP-NP 的治疗效果。该提案中产生的新知识和纳米医学可能会开辟新的治疗途径。用于治疗 AALD。