N-acetylglutamate Synthase: Structure, Function & Defects

N-乙酰谷氨酸合成酶:结构、功能

基本信息

  • 批准号:
    7809804
  • 负责人:
  • 金额:
    $ 55.88万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-09-30 至 2013-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): This is a Competitive Revision Application in response to the Recovery Act Funds Notice Number NOT-OD-09- 058. The parent project over goal is to explore the biology, biochemistry and pathophysiology of N- acetylglutamate synthase (NAGS) is an enzyme that produces the cognate cofactor N-acetylglutamate (NAG), an essential allosteric activator in ureagenesis. This revision application adds two new aims to the parent project. 1. To develop a knockout mouse for NAGS deficiency, characterize its phenotype, and explore its use as a conditional hyperammonemia model. 2. To "isolate" and study the in vivo regulation of ureagenesis specifically at the level of NAGS/CPSI by comparing nitrogen metabolism in N-carbamylglutamate (NCG) treated koNAGS mouse vs. wild type littermates. In addition to these new aims to be completed in two years, this project will enhance in the long term two of the existing aims that study the arginine effects on NAGS function and the effect of naturally-occurring mutations in patients with NAGS deficiency. In this revised project, we will develop, study and make available to the research community a novel "titratable mouse model of hyperammonemia. This knockout NAGS mouse will be rescued with NCG and will develop hyperammonemia upon withdrawal of this cofactor analog. We will determine the in vivo differences between nitrogen balance and metabolism in the NAGS "regulation-deprived" koNAGS mice rescued with NCG vs. the naturally-regulated wild type littermates on and off NCG. These studies will use both gene expression and protein profiles methods and will allow for the first time to "isolate" in vivo the regulatory effects of NAGS on ureagenesis. This project will enhance the pace and quality of the parent grant by providing a new tool for in vivo investigations for our group and other investigators studying hyperammonemia. In addition, The contribution of this project to the economy is leveraged by making the koNGAS mouse model available to othr investigators across the country, enhancing their research and promoting new job creation. PUBLIC HEALTH RELEVANCE: This project is dedicated to the investigation of an important gene and protein (NAGS) that determined how much nitrogen we eliminate from our bodies. It is important to know this since one of the main problem in liver disease is the inability to eliminate toxic nitrogen (ammonia) which can poison the brain. We will study an engineered mouse that does not posses NAGS to allow us to better understand this system and how it is regulated. The results from this project could allow the development of new treatments for elevated ammonia levels to protect the brain from its toxic effects.
描述(由申请人提供):这是一份竞争性修订申请,旨在响应复苏法案基金通知号 NOT-OD-09-058。母项目的总体目标是探索 N-乙酰谷氨酸合酶 (NAGS) 的生物学、生物化学和病理生理学,NAGS 是一种产生同源辅因子 N-乙酰谷氨酸 (NAG) 的酶,NAG 是一种重要的变构酶 尿素生成的激活剂。此修订应用程序向父项目添加了两个新目标。 1. 培育 NAGS 缺陷敲除小鼠,表征其表型,并探索其作为条件性高氨血症模型的用途。 2. 通过比较 N-氨甲酰谷氨酸 (NCG) 处理的 koNAGS 小鼠与野生型同窝小鼠的氮代谢,“分离”并研究尿素生成的体内调节,特别是在 NAGS/CPSI 水平。除了这些将在两年内完成的新目标之外,从长远来看,该项目还将加强现有的两个目标,即研究精氨酸对 NAGS 功能的影响以及自然发生的突变对 NAGS 缺陷患者的影响。在这个修订后的项目中,我们将开发、研究并向研究界提供一种新型的“可滴定的高氨血症小鼠模型”。这种敲除的 NAGS 小鼠将用 NCG 拯救,并在撤回该辅因子类似物后出现高氨血症。我们将确定用 NCG 拯救的 NAGS“调节剥夺”koNAGS 小鼠与用 NCG 拯救的 NAGS“调节剥夺”koNAGS 小鼠体内氮平衡和代谢之间的差异。 NCG 内外自然调节的野生型同窝动物。这些研究将使用基因表达和蛋白质谱方法,并将首次在体内“分离”NAGS 对尿素生成的调节作用。该项目将为我们小组和其他研究高氨血症的研究人员提供体内研究的新工具,从而提高家长资助的速度和质量。此外,该项目对经济的贡献 通过向全国其他研究人员提供 koNGAS 小鼠模型,加强他们的研究并促进创造新的就业机会。 公共健康相关性:该项目致力于研究一个重要的基因和蛋白质 (NAGS),它决定了我们从体内消除了多少氮。了解这一点很重要,因为肝脏疾病的主要问题之一是无法消除可能毒害大脑的有毒氮(氨)。我们将研究一种不具有 NAGS 的工程小鼠,以便我们更好地了解该系统及其调控方式。该项目的结果可能有助于开发针对氨水平升高的新疗法,以保护大脑免受其毒性作用。

项目成果

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Mendel Tuchman其他文献

Mendel Tuchman的其他文献

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{{ truncateString('Mendel Tuchman', 18)}}的其他基金

Overall Adminstration of Rare Diseases Clinical Research Consortia (RDCRC)
罕见病临床研究联盟(RDCRC)的总体管理
  • 批准号:
    8916167
  • 财政年份:
    2015
  • 资助金额:
    $ 55.88万
  • 项目类别:
Pilot/Demonstration Clinical Research Projects Program
试点/示范临床研究项目计划
  • 批准号:
    8916164
  • 财政年份:
    2015
  • 资助金额:
    $ 55.88万
  • 项目类别:
N-acetylglutamate Synthase: Structure, Function & Defects
N-乙酰谷氨酸合成酶:结构、功能
  • 批准号:
    8035600
  • 财政年份:
    2010
  • 资助金额:
    $ 55.88万
  • 项目类别:
N-carbamylglutamate in the treatment of hyperammonemia
N-氨甲酰谷氨酸治疗高氨血症
  • 批准号:
    8061384
  • 财政年份:
    2010
  • 资助金额:
    $ 55.88万
  • 项目类别:
N-CARBAMYLGLUTAMATE (CARBAGLU) IN THE TREATMENT OF HYPERAMMONEMIA
N-氨甲酰谷氨酸(CARBAGLU)治疗高氨血症
  • 批准号:
    8167358
  • 财政年份:
    2010
  • 资助金额:
    $ 55.88万
  • 项目类别:
N-carbamylglutamate in the treatment of hyperammonemia
N-氨甲酰谷氨酸治疗高氨血症
  • 批准号:
    7848468
  • 财政年份:
    2009
  • 资助金额:
    $ 55.88万
  • 项目类别:
N-carbamylglutamate in the treatment of hyperammonemia
N-氨甲酰谷氨酸治疗高氨血症
  • 批准号:
    7505006
  • 财政年份:
    2008
  • 资助金额:
    $ 55.88万
  • 项目类别:
N-carbamylglutamate in the treatment of hyperammonemia
N-氨甲酰谷氨酸治疗高氨血症
  • 批准号:
    8254226
  • 财政年份:
    2008
  • 资助金额:
    $ 55.88万
  • 项目类别:
N-carbamylglutamate in the treatment of hyperammonemia
N-氨甲酰谷氨酸治疗高氨血症
  • 批准号:
    7667880
  • 财政年份:
    2008
  • 资助金额:
    $ 55.88万
  • 项目类别:
N-carbamylglutamate in the treatment of hyperammonemia
N-氨甲酰谷氨酸治疗高氨血症
  • 批准号:
    9036417
  • 财政年份:
    2008
  • 资助金额:
    $ 55.88万
  • 项目类别:

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