Aging as a Risk Factor and Target for Prevention of Liver Cancer

衰老作为肝癌的危险因素和预防目标

• 批准号: 10698098
• 负责人: PETER D. ADAMS
• 金额: $ 258.54万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698098
• 关键词: Age; Age Years; Aging; Benign; Bile Acids; Biochemical Pathway; Body fat; Cells; Cholesterol; Chromatin; Chronic; Cirrhosis; Coupled; DNA Sequence Alteration; Dependence; Disease; Disease Management; Disease Outcome; Early Diagnosis; Epigenetic Process; Equilibrium; Event; Fatty Liver; Fibrosis; Geroscience; Homeostasis; Hypertension; Immune; Immunomodulators; Incidence; Inflammation; Inflammatory; Insulin Resistance; Interferon Activation; Interferons; Intervention; Knowledge; Link; Liver; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Metabolic syndrome; Metabolism; Mitochondria; Molecular; Molecular Profiling; Natural Immunity; Neoplastic liver; Normal tissue morphology; Organism; Pathogenicity; Predisposition; Prevention strategy; Primary carcinoma of the liver cells; Risk; Risk Assessment; Risk Factors; Role; Severities; Signal Transduction; Sirolimus; System; Testing; Tissues; adaptive immunity; age related; aged; assessment application; chronic liver disease; combat; epigenome; immune function; improved; indexing; liver cancer prevention; metabolome; neoplastic; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel therapeutics; permissiveness; prevent; preventive intervention; prognostication; senescence; transcriptome; tumorigenic

PROJECT SUMMARY – OVERALL The incidences of liver cancer (primarily hepatocellular carcinoma (HCC)) are increasing and disease outcome is poor. Consequently, there is an urgent need for new therapies and better preventive strategies. Age is a major risk factor for HCC. In line with the geroscience hypothesis, we hypothesize that aging drives a dysfunctional mitochondrial, epigenetic and metabolic network that promotes and exacerbates age-associated dysregulation of immune function and inflammation in liver. Loss of homeostasis across multiple systems is permissive for neoplastic liver disease. We further hypothesize that dysregulated chronic interferon signaling is central to this pathogenic network. We will dissect this network and test the consequence of chronic interferon signaling, to understand why the incidence of liver cancer increases with age. We will also investigate approaches that target this network for their ability to prevent and combat liver cancer. Our overall specific objectives are: Objective 1. Investigate age-associated changes to mitochondria, chromatin, metabolism (specifically, bile acids) and innate and adaptive immunity, their causal role in HCC and underlying mechanisms. Objective 2. Investigate how interactions between these different systems and age-dependent dysregulation of these interactions contributes to HCC. Objective 3. Test the hypothesis that at least some of these age-associated alterations and consequent predisposition to HCC are dependent on chronic interferon signaling in aged tissue. Objective 4. Investigate approaches that target age dysregulation, for example suppressors of chronic interferon activation, mitohormetic interventions, rapamycin, senolytics, bile acid modulators and immune-modulators, for their ability to suppress the onset of liver cancer and better counter established cancer. Since age is the biggest single risk factor for HCC, it follows that a molecular understanding of the age- dependence of HCC can lead to improved disease management through risk assessment, early detection, prognostication and therapy. Moreover, an understanding of how HCC develops during aging can also lead to preventative interventions. This PPG will define critical molecular mechanisms underpinning age-dependence of HCC. We will also promote approaches for improved risk assessment through application, testing and refinement of a transcriptome-based “tumorigenic index” to quantitate the risk of HCC. Finally, based on our discoveries, we will test a panel of candidate interventions for those that can prevent and combat HCC.

项目概要——总体 肝癌（主要是肝细胞癌（HCC））的发病率正在增加，并且疾病结果 很穷。因此，迫切需要新的疗法和更好的预防策略。年龄是一个主要因素 HCC 的危险因素。根据老年科学假说，我们假设衰老会导致功能失调 线粒体、表观遗传和代谢网络促进和加剧与年龄相关的失调 免疫功能和肝脏炎症。跨多个系统失去稳态是允许的 肿瘤性肝病。我们进一步假设慢性干扰素信号传导失调是这一现象的核心 致病网络。我们将剖析这个网络并测试慢性干扰素信号传导的结果，以 了解为什么肝癌的发病率随着年龄的增长而增加。我们还将研究针对目标的方法 该网络因其预防和对抗肝癌的能力而闻名。我们的总体具体目标是： 目标 1. 研究与年龄相关的线粒体、染色质、代谢（特别是胆汁酸）变化 以及先天性和适应性免疫，它们在 HCC 中的因果作用和潜在机制。 目标 2. 研究这些不同系统之间的相互作用以及年龄依赖性失调 这些相互作用会导致 HCC。 目标 3. 检验以下假设：至少有一些与年龄相关的改变及其后果 肝癌的易感性取决于衰老组织中的慢性干扰素信号传导。 目标 4. 研究针对年龄失调的方法，例如慢性干扰素抑制剂 激活、线粒体激素干预、雷帕霉素、senolytics、胆汁酸调节剂和免疫调节剂， 它们能够抑制肝癌的发作并更好地对抗已形成的癌症。 由于年龄是 HCC 最大的单一危险因素，因此对年龄的分子理解 HCC 的依赖性可以通过风险评估、早期发现、 预测和治疗。此外，了解衰老过程中 HCC 如何发展也可以导致 预防性干预措施。该 PPG 将定义支撑年龄依赖性的关键分子机制 肝癌。我们还将推广通过应用、测试和细化改进风险评估的方法 基于转录组的“致瘤指数”来量化 HCC 风险。最后，根据我们的发现， 我们将测试一组候选干预措施，以预防和对抗 HCC。