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Innovative Genetic Approaches to Enhance Liver Repopulation and Reduce Cancer Risk and Progression

增强肝脏再生并降低癌症风险和进展的创新遗传学方法

基本信息

批准号：
10434813
负责人：
KLAUS H KAESTNER
金额：
$ 53.34万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10434813
关键词：
Acute Acute Liver Failure Attenuated BAY 54-9085 Biological Models Clinical Treatment Complementary DNA DNA Data Development Disease Early Diagnosis Evaluation FDA approved Genes Genetic Genetic Screening Genotype Grant Growth Health Hepatic Hepatocyte High-Throughput Nucleotide Sequencing Human Individual Injury Investigation Knockout Mice Length Libraries Liver Liver Extract Liver Regeneration Liver diseases Malignant Neoplasms Malignant neoplasm of liver Maps MicroRNAs Modeling Mus Mutation Natural regeneration Neoplasms Oncogenes Oncogenic Partial Hepatectomy Pathway interactions Patients Pharmacotherapy Phenotype Plasmids Porifera Prevention Primary carcinoma of the liver cells Process Prognosis Recovery Resistance Risk Role Survival Rate TP53 gene Technology Testing The Cancer Genome Atlas Toxic Hepatitis Transforming Growth Factor alpha Tumor Burden Tyrosine Kinase Inhibitor United States Xenograft Model Xenograft procedure acetaminophen overdose acute liver injury base cancer prevention cancer risk chronic liver disease chronic liver injury effective therapy genetic approach genetic makeup hepatocellular carcinoma cell line improved in vivo inhibitor innovation liver cancer model liver cell proliferation liver injury mimetics mouse model nanoparticle new combination therapies novel novel therapeutics overexpression prevent response screening small hairpin RNA therapeutic target tumor tumor growth tumor initiation tumor progression tumorigenesis

项目摘要

A better understanding of the liver’s response to toxic injury, which includes hepatocyte proliferation, and – unfortunately – an increased risk for hepatocellular carcinoma (HCC), is a prerequisite for the development of novel clinical treatments for chronic liver disease and improved cancer prevention. Existing drug therapies for HCC such as sorafenib extend patient survival by only three months. We recently developed a massively parallel in vivo screening platform to test the impact of genetic factors such as full-length cDNAs or miRNAs on liver repopulation and tumorigenesis. We have used this screening technology to build a map of all miRNAs active in liver regeneration. Here, we propose to exploit this innovative paradigm to conduct a comprehensive evaluation of the effects of the 135 most abundant but evolutionarily conserved hepatic miRNAs on the processes of recovery from toxic liver injury and HCC tumorigenesis. In Specific Aim 1, we will determine the combined benefits of three miRNAs identified in our prior screen on liver repopulation following toxic injuries, as a step toward using miRNA-mimetic drug therapies for liver diseases. This will be accomplished through delivery of miRNA-encoding plasmids or nanoparticles singly and in all combination. In Specific Aim 2, we will determine the impact of hepatic miRNAs and miRNA combinations on HCC tumor development in vivo. To this end, we have developed two models of rapid HCC development in mice, in which we will screen our library of 135 ‘tough decoys’ (“TuD’s”), or inhibitors of miRNA action, on tumor formation. We will quantify the abundance of all TuD’s using high throughput sequencing in the tumor-loaded liver compared to the input library. TuD’s enriched in after tumor formation target miRNAs that normally limit tumor growth, and those found less abundant target miRNAs that promote tumorigenesis. We will then test the combinations of the most potent miRNA effectors on tumor formation following systemic delivery. In Specific Aim 3 we will perform a conditional screen of miRNAs that impact Sorafenib resistance to identify novel combination treatments for the prevention or treatment of HCC. Together, our powerful genetic screens promise to identify miRNA effectors that can be employed for the treatment of acute liver injury and, in combination with Sorafenib, as a more effective treatment to prevent HCC initiation and progression.

更好地了解肝脏对毒性损伤的反应，包括肝细胞增殖，不幸的是，肝细胞癌 (HCC) 风险增加是开发慢性肝病的新型临床治疗方法并改善癌症预防。现存的 HCC 药物治疗（如索拉非尼）只能将患者的生存期延长三个月。我们最近开发了大规模并行体内筛选平台，用于测试遗传因素（例如全长 cDNA 或 miRNA 对肝脏再生和肿瘤发生的影响。我们已经使用这种筛选技术来构建所有的地图 miRNA 活跃于肝脏再生。在这里，我们建议利用这种创新范式进行综合评估 135 个最丰富但进化上保守的肝脏的影响 miRNA 对中毒性肝损伤和 HCC 肿瘤发生恢复过程的影响。在具体目标 1 中，我们将确定我们之前筛选中确定的三种 miRNA 对肝脏再生的综合益处，如下毒性损伤，作为使用 miRNA 模拟药物治疗肝脏疾病的一步。这将是通过单独或全部组合递送 miRNA 编码质粒或纳米粒子来完成。在具体目标2，我们将确定肝脏miRNA和miRNA组合对HCC肿瘤的影响体内发育。为此，我们开发了两种小鼠 HCC 快速发展模型，其中我们将筛选 135 个“强诱饵”（“TuD”）或 miRNA 作用抑制剂对肿瘤形成的库。我们将使用高通量测序在负载肿瘤的肝脏中量化所有 TuD 的丰度与输入库相比。 TuD 富含肿瘤形成后通常限制肿瘤的靶 miRNA 生长，以及发现促进肿瘤发生的靶标 miRNA 含量较低的情况。然后我们将测试全身递送后对肿瘤形成最有效的 miRNA 效应子的组合。具体来说目标 3 我们将对影响索拉非尼耐药性的 miRNA 进行条件筛选，以鉴定新的用于预防或治疗 HCC 的联合治疗。一起，我们强大的基因筛选承诺鉴定可用于治疗急性肝损伤的 miRNA 效应子，并在与索拉非尼联合使用，作为预防 HCC 发生和进展的更有效治疗方法。