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: 10674036
• 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/10674036
• 关键词: ATM Signaling Pathway; ATM activation; ATM gene; Acceleration; 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; Connexin 43; DNA; DNA Damage; DNA Double Strand Break; DNA lesion; 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; Institution; Investigation; Knowledge; 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; Pharmaceutical Preparations; Phase; Phosphotransferases; Physicians; Physiological Processes; Polyploidy; Population; Predisposition; Prevalence; Primary carcinoma of the liver cells; Process; Protein Kinase; Proteins; Publishing; Reproducibility; Research; Research Training; Risk; Role; Sampling; Scientist; Signal Transduction; Site; Steatohepatitis; Stress; TACSTD1 gene; Technology; Testing; Therapeutic; Toxic effect; Toxin; Transforming Growth Factor beta; Translational Research; Tyrosinemias; Work; adduct; ataxia telangiectasia mutated protein; career development; cell growth; cell injury; chronic liver disease; clinical practice; clinical training; cohort; differential expression; 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; 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）会显着增加肝硬化的风险， 肝细胞癌和肝功能衰竭。在儿童中，PNAFLD 的进展速度可能比成人快得多， 了解这一点很重要，但这种疾病恶化的机制尚不清楚。活跃的肝脏 成长是儿童的一个独特的方面；然而，这种生理过程是否会影响结果 尚未对 PNAFLD 进行研究。为了解决 PNAFLD 肝损伤和修复的根本基础，我 获得了将肝再生机制纳入基础和转化研究的基础 肝脏 DNA 损伤和炎症的总体背景。我的工作导致共济失调性毛细血管扩张突变（ATM） 基因和下游分子途径调节肝DNA损伤反应，包括细胞生长- 肝损伤后的停滞是肝再生的关键障碍。我最近发表的针对成人的研究 NAFLD 证实获得性 ATM 功能不全是从脂肪肝进展为脂肪肝的关键因素 纳什。由于基因组和线粒体 DNA 的完整性对于出生后肝脏的生长和发育至关重要。 随后的器官健康，然后我假设肝脏生长过程中 ATM 失调会产生 对 PNAFLD 的负面影响。在这个提案中，我通过两个相互关联的目标来开发这种可能性。在 具体目标 1，我测试 ATM 失调会损害肝脏修复和再生的假设 PNALFD。这将通过对脂肪肝中现有的肝脏样本进行详细分析来推进 布朗克斯的诊所队列。 ATM 信号在细胞事件和过程中的作用 PNAFLD 将通过基于阵列的技术和功能基因组学方法进行差异识别 表达 mRNA 和蛋白质。与祖细胞相关的肝再生的其他机制 儿童肝脏生长中普遍存在的群体将通过强大的基于细胞的检测进行检查。在具体目标中 2、我将采用分子功能丧失的方法来实验开发和验证ATM的作用。 这将结合一种新的 PNAFLD 小鼠模型，通过高脂肪饮食和 肝脏生长期的化学损伤。该模型的人类特定相关性将得到证实。 我已做好充分准备，具有适当的临床和研究培训背景来开展这项研究 尽管这个 K-08 奖项将有助于进一步提高调查职业发展的技能。这个提议 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技能。加上杰出的机构承诺 和环境，这种职业发展努力将增加外部资金目标的潜力 分子途径特异性病理生理学和治疗研究，以促进儿科健康。