Novel gene discovery in disorders of the liver and biliary tree

肝脏和胆管系统疾病的新基因发现

基本信息

  • 批准号:
    10552553
  • 负责人:
  • 金额:
    $ 16.38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-01-19 至 2026-11-30
  • 项目状态:
    未结题

项目摘要

This career development award details a 5-year training plan to facilitate transition to an independent career as a hepatogeneticist focused on gene discovery and characterization for hepatobiliary disease. I completed my Pediatrics residency at St. Christopher’s Hospital for Children and my fellowship in Human Genetics at The Children’s Hospital of Philadelphia (CHOP). I am currently an attending physician and research fellow at CHOP in the Division Of Human Genetics. My clinical and research efforts focus on children with hepatobiliary disease. My goals for this proposal are to become more experienced with exome and genetic variant interpretation and to gain experience using zebrafish as a model to study hepatobiliary disease. I will also use this opportunity to develop my ability to design experiments, write successful grant applications, and lead a laboratory, to facilitate a smooth transition to academic faculty. My mentor for this proposal is Dr. Hakon Hakonarson, a Professor of Pediatrics and director of the Center for Applied Genomics (CAG) at CHOP. Dr. Hakonarson has mentored dozens of post-doctoral research fellows and K-awardees, and was the recipient of CHOP’s Research Mentor Award. I will be co-mentored by Dr. Michael Pack, a Professor of Medicine at the University of Pennsylvania (UPenn). Dr. Pack also has an extensive history of mentoring trainees and K-awardees and works closely with Dr. Hakonarson on novel gene characterization. I have also assembled a scientific advisory committee, consisting of Drs. Klaus Kaestner, Ben Stanger, Kirk Wangensteen, Tom Jongens, and Elizabeth Rand, all experts in the fields of hepatology, neurogenetics or genetics with extensive mentoring experience. I will also have the benefit of the outstanding resources at both CHOP and UPenn, which have facilitated career development for countless past trainees. My proposed research focusses on the discovery and characterization of novel genes implicated in hepatobiliary disease. We are assembling a cohort of individuals with unexplained hepatobiliary disease, and will apply a research pipeline to facilitate identification of novel genes. Our laboratory has already identified de novo nonsense and frameshift variants in MED12 as causal for Hardikar Syndrome, a syndromic form of biliary dysgenesis, of previously unknown genetic basis. Aim 1 of this proposal delineates how a patient cohort will be assembled and characterized, and Aim 2 details the characterization of the role of MED12 in biliary development. Completion of the proposed studies will improve our ability to genetically diagnose hepatobiliary disease, better characterize the genetic landscape of these poorly-understood conditions, and elucidate the mechanism by which nonsense and frameshift MED12 variants cause biliary disease. This proposal will also provide me with experience studying hepatobiliary disease in animal and cellular models, writing grants and scientific papers, and allow me to observe how academic laboratories are run. Furthermore, this patient cohort and the cellular and animal models developed as part of this proposal will be invaluable in my future career.
这项职业发展奖详细介绍了一项为期5年的培训计划,以促进向独立职业生涯的过渡 一位肝脏遗传学家专注于肝胆疾病的基因发现和特征描述。我完成了我的 圣克里斯托弗儿童医院的儿科住院医师和我在圣克里斯托弗儿童医院的人类遗传学研究员 费城儿童医院(CHOP)。我目前是CHOP的主治医师和研究员。 在人类遗传学分部。我的临床和研究工作主要针对患有肝胆疾病的儿童。 我对这项提议的目标是对外显子组和基因变体的解释更有经验 为利用斑马鱼作为研究肝胆疾病的动物模型积累经验。我也将利用这个机会 培养我设计实验的能力,撰写成功的拨款申请,并领导实验室,以促进 顺利过渡到教职员工。 我这项提议的导师是哈康·哈科纳森博士,他是儿科学教授兼美国儿科中心主任 应用基因组学(CAG)。Hakonarson博士指导了数十名博士后研究员和 K奖获得者,并获得了CHOP的研究导师奖。我将由迈克尔博士共同指导 宾夕法尼亚大学(UPenn)医学教授帕克说。帕克博士也有广泛的病史 指导受训者和K奖获得者,并与Hakonarson博士在新的基因表征方面密切合作。我 还成立了一个科学咨询委员会,由Klaus Kaestner博士、Ben Stanger博士、Kirk博士组成 王根斯汀、汤姆·容金斯和伊丽莎白·兰德,都是肝病学、神经遗传学或 具有丰富指导经验的遗传学专业人士。我还将受益于这两家公司的杰出资源 Chop和UPenn,这促进了无数过去的实习生的职业发展。 我建议的研究重点是发现和表征与肝胆管相关的新基因 疾病。我们正在收集一组患有不明原因肝胆疾病的患者,并将应用一种 研究流水线,以促进新基因的识别。我们的实验室已经鉴定出从头开始 MED12基因的无义和移码变异导致Hardikar综合征--胆道的一种综合征形式 发育不全,之前未知的遗传基础。这项提案的目标1描述了患者队列将如何 目的2详细描述了MED12在胆道发育中的作用。 拟议研究的完成将提高我们从基因上诊断肝胆疾病的能力,更好地 描述这些鲜为人知的疾病的遗传格局,并通过以下方式阐明其机制 哪些无稽之谈和移码MED12变异会导致胆道疾病。这项提议还将为我提供 在动物和细胞模型中研究肝胆疾病,撰写补助金和科学论文的经验, 请允许我观察一下学术实验室是如何运行的。此外,这个患者队列和细胞 作为这项提议的一部分而开发的动物模型将在我未来的职业生涯中发挥无价的作用。

项目成果

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Alanna Strong其他文献

Alanna Strong的其他文献

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{{ truncateString('Alanna Strong', 18)}}的其他基金

Novel gene discovery in disorders of the liver and biliary tree
肝脏和胆管系统疾病的新基因发现
  • 批准号:
    10370717
  • 财政年份:
    2022
  • 资助金额:
    $ 16.38万
  • 项目类别:

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