Ataxia Telangiectasia Mutated (ATM)-mediated hepatic DNA damage in pediatric nonalcoholic fatty liver disease

共济失调毛细血管扩张突变 (ATM) 介导的儿童非酒精性脂肪性肝病中的肝 DNA 损伤

• 批准号: 10301928
• 负责人: Preeti Viswanathan
• 金额: $ 16.87万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10301928
• 关键词: ATM Signaling Pathway; ATM activation; ATM gene; Acetaminophen; Acute Liver Failure; Address; Adolescence; Adult; Affect; Automobile Driving; Award; Basic Science; Bioinformatics; Biological Assay; Biopsy; Birth; Body Weight; Cell Cycle; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cessation of life; Chemical Injury; Chemicals; Child; Childhood; Cirrhosis; Clinic; Clinical; Clinical Research; Consequentialism; DNA; DNA Damage; DNA Double Strand Break; DNA lesion; DNA-dependent protein kinase; Development Plans; Disease; Disease Management; Disease Progression; Elements; Environment; Event; Excision; Extramural Activities; Fatty Liver; Fibrosis; Functional disorder; Funding; Genes; Genetic; Genome; Genomic DNA; Genomic approach; Growth; Health; Hepatic; Hepatocyte; High Fat Diet; High Prevalence; Histologic; Human; Impairment; Inflammation; Inflammatory; Injury; Investigation; Knowledge; Lead; Leadership; Lipids; Liver; Liver Failure; Liver Regeneration; Malignant Neoplasms; Mediating; Mentors; Messenger RNA; Metabolic; Metabolism; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Molecular Epidemiology; Molecular Target; Mus; NBS1 gene; Natural regeneration; Nuclear; Obesity; Oncogenic; Organ; Outcome; Oxidative Stress; Pathway interactions; Peroxides; Pharmaceutical Preparations; Phase; Phosphotransferases; Physicians; Physiological Processes; Polyploidy; Population; Predisposition; Prevalence; Primary carcinoma of the liver cells; Process; Proliferating; Protein Kinase; Proteins; Publishing; Reproducibility; Research; Research Training; Risk; Role; Sampling; Scientist; Signal Transduction; Site; Steatohepatitis; TACSTD1 gene; Technology; Testing; Therapeutic; Toxic effect; Toxin; Transforming Growth Factor beta; Translational Research; Tyrosinemias; Work; adduct; ataxia telangiectasia mutated protein; base; career development; cell growth; cell injury; chronic liver disease; clinical practice; cohort; differential expression; ds-DNA; early childhood; epigenomics; fetal; fibrogenesis; functional genomics; genome integrity; improved outcome; infancy; injury and repair; knock-down; liver biopsy; liver cell proliferation; liver injury; liver repair; loss of function; mRNA Expression; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; obesity in children; pediatric non-alcoholic fatty liver disease; postnatal; progression marker; reconstitution; repaired; replication stress; response; skills; stem cell biology; stem cell survival; stem cells

Pediatric nonalcoholic fatty liver disease (PNAFLD) is the leading cause of chronic liver disease in childhood. Progression from fatty liver (FL) to steatohepatitis (NASH) significantly increases risks for cirrhosis, hepatocellular carcinoma and liver failure. In children, PNAFLD may progress far more rapidly than in adults, which is important to understand but mechanisms underlying this disease worsening are unknown. Active liver growth is a unique aspect in children; however, whether this physiological process may affect outcomes in PNAFLD has not been studied. To address the fundamental basis of hepatic injury and repair in PNAFLD, I obtained grounding in basic and translational research incorporating liver regeneration mechanisms within the overall context of hepatic DNA damage and inflammation. My work led to ataxia telangiectasia mutated (ATM) gene and downstream molecular pathway in regulating hepatic DNA damage response, including cell growth- arrest after hepatic injury as a critical barrier to liver regeneration. My recently published study in adults with NAFLD substantiated that acquired ATM insufficiency is a critical element in progression from fatty liver to NASH. Since the integrity of genomic and mitochondrial DNA is critical for postnatal liver growth and subsequent organ health, I then hypothesized that ATM dysregulation during hepatic growth will exert a negative impact on PNAFLD. In this proposal, I develop this possibility through two interrelated objectives. In specific Aim 1, I test the hypothesis that ATM dysregulation will impair liver repair and regeneration in PNALFD. This will be advanced through detailed analysis of already available liver samples from our fatty liver clinic cohort in the Bronx. The role of ATM signaling in cellular events and processes during progression of PNAFLD will be identified by array-based technologies and functional genomics approaches for differentially expressed mRNAs and proteins. Additional mechanisms for liver regeneration related to progenitor cell populations prevalent in growing liver of children will be examined in robust cell-based assays. In specific Aim 2, I will employ molecular loss-of-function approach to experimentally develop and validate the role of ATM. This will incorporate a novel mouse model for PNAFLD with disease induction through high fat diet and chemical injury during hepatic growth phase. The human-specific relevance of this model will be substantiated. I am well-prepared to conduct this research with appropriate clinical and research training background although this K-08 award will help advance further skill sets for investigative career development. This proposal incorporates exceptional mentoring team and advisors, including world-class expertise in liver regeneration, stem cell biology, molecular epidemiology, and epigenomics. I have formulated a targeted career development plan to advance my scientific capacity and leadership skills. Together with outstanding institutional commitment and environment, this career development effort will increase potential for extramural funding targeting molecular pathway-specific pathophysiological and therapeutic investigations to advance pediatric health.

小儿非酒精脂肪肝病（PNAFLD）是儿童慢性肝病的主要原因。 从脂肪肝（FL）到脂肪性肝炎（NASH）的进展显着增加了肝硬化的风险， 肝细胞癌和肝衰竭。在儿童中，PNAFLD可能比成年人更快地进展 重要的是要理解，但是这种疾病恶化的机制尚不清楚。活性肝 成长是儿童的独特方面。但是，这种生理过程是否会影响 尚未研究PNAFLD。为了解决PNAFLD肝损伤和修复的基本基础，我 在基础和转化研究中获得了基础，该研究结合了肝脏再生机制 肝DNA损伤和炎症的总体背景。我的工作导致了触发性毛细血管炎突变（ATM） 基因和下游分子途径在调节肝DNA损伤反应时，包括细胞生长 - 肝损伤后被捕，这是肝脏再生的关键障碍。我最近在成年人中发表的研究 NAFLD证实了获得的ATM功能不全是从脂肪肝发展到的关键因素 纳什。由于基因组和线粒体DNA的完整性对于产后肝生长和 随后的器官健康，我假设在肝增长过程中的ATM失调会发挥 对PNAFLD的负面影响。在此提案中，我通过两个相互关联的目标发展了这种可能性。在 特定目的1，我检验了以下假设：ATM失调会损害肝脏修复和再生 pnalfd。这将通过详细分析我们脂肪肝的肝样品进行详细分析 布朗克斯的诊所队列。 ATM信号在蜂窝事件和过程中的作用 PNAFLD将通过基于数组的技术和功能基因组学方法来鉴定差异化 表示mRNA和蛋白质。与祖细胞有关的肝脏再生的其他机制 基于稳健的细胞测定法，将检查成长中的儿童肝脏的种群。在特定目标中 2，我将采用分子功能丧失方法来实验开发和验证ATM的作用。 这将通过高脂肪饮食和 肝生长阶段的化学损伤。该模型的人类特定相关性将得到证实。 我很准备在适当的临床和研究培训背景下进行这项研究 尽管该K-08奖将有助于提高调查职业发展的进一步技能。这个建议 纳入杰出的指导团队和顾问，包括肝脏再生方面的世界一流专业知识， 干细胞生物学，分子流行病学和表观基因组学。我已经制定了有针对性的职业发展 计划提高我的科学能力和领导能力。以及杰出的机构承诺 和环境，这项职业发展工作将增加针对校外资金的潜力 分子途径特异性的病理生理和治疗研究，以提高小儿健康。