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

基本信息

  • 批准号:
    10475172
  • 负责人:
  • 金额:
    $ 16.72万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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。

项目成果

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Preeti Viswanathan其他文献

Preeti Viswanathan的其他文献

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{{ truncateString('Preeti Viswanathan', 18)}}的其他基金

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
  • 财政年份:
    2021
  • 资助金额:
    $ 16.72万
  • 项目类别:
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
  • 财政年份:
    2021
  • 资助金额:
    $ 16.72万
  • 项目类别:

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