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: 10475172
• 负责人: Preeti Viswanathan
• 金额: $ 16.72万
• 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/10475172
• 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 inflammation; 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; simple steatosis; 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.

儿童非酒精性脂肪性肝病（PNAFLD）是儿童慢性肝病的主要原因。 从脂肪肝（FL）进展为脂肪性肝炎（NASH）显著增加了肝硬化的风险， 肝细胞癌和肝功能衰竭。在儿童中，PNAFLD的进展可能比成人快得多， 这一点很重要，但这种疾病恶化的机制尚不清楚。活动性肝 生长是儿童的一个独特方面;然而，这一生理过程是否会影响儿童的结局， PNAFLD尚未研究。为了阐明PNAFLD肝损伤和修复的基本基础， 在基础和转化研究中获得基础，将肝再生机制纳入 肝脏DNA损伤和炎症的整体背景。我的工作导致共济失调毛细血管扩张症突变（ATM） 基因和下游分子途径调节肝DNA损伤反应，包括细胞生长- 作为肝再生的关键屏障。我最近发表的一项研究， NAFLD证实，获得性ATM功能不全是脂肪肝进展至 纳什由于基因组和线粒体DNA的完整性对出生后肝脏生长至关重要， 随后的器官健康，然后我假设在肝脏生长过程中ATM失调将产生 对PNAFLD的负面影响。在这个建议中，我通过两个相互关联的目标来发展这种可能性。在 具体目标1，我测试的假设，ATM失调将损害肝修复和再生， PNALFD。这将通过对我们脂肪肝的现有肝脏样本进行详细分析来推进 在布朗克斯的诊所队列中。ATM信号转导在肿瘤进展过程中的细胞事件和过程中的作用 PNAFLD将通过基于芯片的技术和功能基因组学方法进行鉴定， 表达的mRNA和蛋白质。与祖细胞相关的肝再生的其他机制 将在稳健的基于细胞的测定中检查儿童生长肝脏中普遍存在的群体。具体目标 2、采用分子功能丧失的方法，实验性地开发和验证ATM的作用。 这将包括一种新的PNAFLD小鼠模型，通过高脂肪饮食诱导疾病， 肝脏生长期的化学损伤。该模型的人类特定的相关性将得到证实。 我已经为开展本研究做好了充分的准备，具有适当的临床和研究培训背景 虽然这个K-08奖项将有助于进一步提高调查职业发展的技能。这项建议 拥有卓越的指导团队和顾问，包括世界一流的肝再生专业知识， 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 计划提高我的科学能力和领导能力。加上出色的机构承诺， 和环境，这种职业发展的努力将增加潜在的校外资金的目标 分子途径特定的病理生理和治疗研究，以促进儿科健康。