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:
- 金额:$ 53.34万
- 依托单位:
- 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:
- 关键词:AcuteAcute Liver FailureAttenuatedBAY 54-9085Biological ModelsClinical TreatmentComplementary DNADNADataDevelopmentDiseaseEarly DiagnosisEvaluationFDA approvedGenesGeneticGenetic ScreeningGenotypeGrantGrowthHealthHepaticHepatocyteHigh-Throughput Nucleotide SequencingHumanIndividualInjuryInvestigationKnockout MiceLengthLibrariesLiverLiver ExtractLiver RegenerationLiver diseasesMalignant NeoplasmsMalignant neoplasm of liverMapsMicroRNAsModelingMusMutationNatural regenerationNeoplasmsOncogenesOncogenicPartial HepatectomyPathway interactionsPatientsPharmacotherapyPhenotypePlasmidsPoriferaPreventionPrimary carcinoma of the liver cellsProcessPrognosisRecoveryResistanceRiskRoleSurvival RateTP53 geneTechnologyTestingThe Cancer Genome AtlasToxic HepatitisTransforming Growth Factor alphaTumor BurdenTyrosine Kinase InhibitorUnited StatesXenograft ModelXenograft procedureacetaminophen overdoseacute liver injurybasecancer preventioncancer riskchronic liver diseasechronic liver injuryeffective therapygenetic approachgenetic makeuphepatocellular carcinoma cell lineimprovedin vivoinhibitorinnovationliver cancer modelliver cell proliferationliver injurymimeticsmouse modelnanoparticlenew combination therapiesnovelnovel therapeuticsoverexpressionpreventresponsescreeningsmall hairpin RNAtherapeutic targettumortumor growthtumor initiationtumor progressiontumorigenesis
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
KLAUS H KAESTNER其他文献
KLAUS H KAESTNER的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('KLAUS H KAESTNER', 18)}}的其他基金
The role of senescent beta cells in T1D and T2D
衰老 β 细胞在 T1D 和 T2D 中的作用
- 批准号:
10583684 - 财政年份:2022
- 资助金额:
$ 53.34万 - 项目类别:
The role of senescent beta cells in T1D and T2D
衰老 β 细胞在 T1D 和 T2D 中的作用
- 批准号:
10708994 - 财政年份:2022
- 资助金额:
$ 53.34万 - 项目类别:
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
- 批准号:
10217062 - 财政年份:2020
- 资助金额:
$ 53.34万 - 项目类别:
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
- 批准号:
10654627 - 财政年份:2020
- 资助金额:
$ 53.34万 - 项目类别:
The Human Pancreas Analysis Program for Type 2 Diabetes
2 型糖尿病人类胰腺分析项目
- 批准号:
10252957 - 财政年份:2019
- 资助金额:
$ 53.34万 - 项目类别:
The Human Pancreas Analysis Program for Type 2 Diabetes
2 型糖尿病人类胰腺分析项目
- 批准号:
10020973 - 财政年份:2019
- 资助金额:
$ 53.34万 - 项目类别:
The Human Pancreas Analysis Program for Type 2 Diabetes
2 型糖尿病人类胰腺分析项目
- 批准号:
10675236 - 财政年份:2019
- 资助金额:
$ 53.34万 - 项目类别:
The Human Pancreas Analysis Program for Type 2 Diabetes
2 型糖尿病人类胰腺分析项目
- 批准号:
10568985 - 财政年份:2019
- 资助金额:
$ 53.34万 - 项目类别:
The Human Pancreas Analysis Program for Type 2 Diabetes
2 型糖尿病人类胰腺分析项目
- 批准号:
10261669 - 财政年份:2019
- 资助金额:
$ 53.34万 - 项目类别:
Regulatory cascades in gastrointestinal proliferation
胃肠道增殖的调节级联反应
- 批准号:
9474868 - 财政年份:2017
- 资助金额:
$ 53.34万 - 项目类别:
相似海外基金
Senescent hepatocytes mediate reprogramming of immune cells in acute liver failure
衰老肝细胞介导急性肝衰竭中免疫细胞的重编程
- 批准号:
10679938 - 财政年份:2023
- 资助金额:
$ 53.34万 - 项目类别:
Hepatocytes Encapsulated with mesenchymal stromal cells in alginate microbeads for the treatment of acute Liver failure in Paediatric patients (HELP)
将间充质基质细胞封装在藻酸盐微珠中的肝细胞用于治疗儿科患者的急性肝衰竭(HELP)
- 批准号:
MR/V038583/1 - 财政年份:2022
- 资助金额:
$ 53.34万 - 项目类别:
Research Grant
Development of the innovative treatment using self iPS cell for acute liver failure
开发利用自身 iPS 细胞治疗急性肝衰竭的创新疗法
- 批准号:
21K08685 - 财政年份:2021
- 资助金额:
$ 53.34万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Pediatric Acute Liver Failure Immune Response Network (PALF IRN): Treatment for Immune Mediated Pathophysiology (TRIUMPH)
小儿急性肝衰竭免疫反应网络 (PALF IRN):免疫介导的病理生理学治疗 (TRIUMPH)
- 批准号:
10421290 - 财政年份:2021
- 资助金额:
$ 53.34万 - 项目类别:
Pediatric Acute Liver Failure Immune Response Network (PALF IRN): Treatment for Immune Mediated Pathophysiology (TRIUMPH)
小儿急性肝衰竭免疫反应网络 (PALF IRN):免疫介导的病理生理学治疗 (TRIUMPH)
- 批准号:
10180251 - 财政年份:2021
- 资助金额:
$ 53.34万 - 项目类别:
Therapeutic effect of plasmacytoid dendritic cells transplantation for acute liver failure
浆细胞样树突状细胞移植治疗急性肝衰竭的疗效
- 批准号:
20K21607 - 财政年份:2020
- 资助金额:
$ 53.34万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
Macrophage Therapy for Acute Liver Failure
巨噬细胞治疗急性肝衰竭
- 批准号:
MR/T044802/1 - 财政年份:2020
- 资助金额:
$ 53.34万 - 项目类别:
Research Grant
Investigation of an optimal environment for the proliferation of mature hepatocytes toward the rescue of acute liver failure patients
研究成熟肝细胞增殖的最佳环境以挽救急性肝衰竭患者
- 批准号:
19K08475 - 财政年份:2019
- 资助金额:
$ 53.34万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Pediatric Acute Liver Failure (PALF) TReatment for ImmUne Mediated PathopHysiology (TRIUMPH)
小儿急性肝衰竭 (PALF) 免疫介导病理生理学治疗 (TRIUMPH)
- 批准号:
9789253 - 财政年份:2018
- 资助金额:
$ 53.34万 - 项目类别:
Cryopreservation of hiPS-derivd hepatic progenitor cells and application to acute liver failure treatment
hiPS源性肝祖细胞的冷冻保存及其在急性肝衰竭治疗中的应用
- 批准号:
18K08662 - 财政年份:2018
- 资助金额:
$ 53.34万 - 项目类别:
Grant-in-Aid for Scientific Research (C)