CANAVAN DISEASE PATHOGENESIS AND TREATMENT

卡纳万病的发病机制和治疗

基本信息

项目摘要

DESCRIPTION (adapted from applicant's abstract): Canavan disease (CD) is an autosomal-recessive neurodegenerative disorder that develops after birth and results in death usually before age 10. CD is found worldwide, but the majority of patients so far identified are of Ashkenazi Jewish descent. The CD carrier frequency in this population is estimated to be 1 in 38, which is as high as that of Tay Sachs disease. CD is caused by mutations in the gene coding for the enzyme aspartoacylase (ASPA) that degrades N-acetylaspartate (NAA), a highly abundant (5-10 mM) and nervous system specific metabolite, into acetate and aspartate. However, neither the pathogenesis of CD nor the functions of NAA have been defined. Further, no animal model for exploration of potential treatment for CD is available. The investigators propose to make a mouse model for CD and test the hypothesis that CD pathogenesis involves reduced availability of NAA-derived acetate for fatty acid/lipid synthesis during myelination. Making the animal model for CD involves generating heterozygous and homozygous mice in which the ASPA gene is knocked out. Development of CD will be confirmed using a behavioral test and subsequent light and electron microscopic analysis of the brain. The hypothesis mentioned above will be tested in the animal model by determining whether or not treatment with acetate, a fatty acid precursor which can easily enter brain, prevents development of CD in the animal model. Based on the endogenous and nontoxic nature of acetate, and the urgency for a treatment for CD, acetate administration will be optimized in normal mice with regard to dosage and safety to enable clinical trials of acetate as soon as possible. Toward these goals, they have successfully cloned and expressed mouse ASPA cDNA by a PCR strategy, and have identified an artificial bacterial chromosome containing the complete ASPA gene. Sequencing of the genomic clone is in progress. Successful completion of the proposed study would establish the use of acetate for the treatment of CD. Further, the methodological innovations of the proposed study will have a major impact in the field by stimulating research into the nervous system specific roles of NAA and N-acetylaspartylglutamate, a putative neurotransmitter derived from NAA.
描述(摘自申请者的摘要):Canavan病(CD)是一种 常染色体隐性遗传性神经退行性疾病,在出生后和 通常在10岁之前导致死亡。CD在世界各地都有发现,但大多数 到目前为止确认的患者中有德系犹太人后裔。CD载体 据估计,这一人群的频率为每38人中有1人,这一比例高达 泰·萨克斯病。CD是由编码基因突变引起的 天冬氨酸氨基转移酶(ASPA)是一种高效降解N-乙酰天冬氨酸(NAA)的酶 丰富的(5-10 mm)和神经系统特异的代谢物,转化为醋酸盐和 天冬氨酸。然而,无论是CD的发病机制,还是NAA的功能 已经被定义了。此外,没有探索潜力的动物模型 对CD的治疗是可用的。研究人员提议制作一只小鼠模型 对于CD,并检验CD发病机制涉及减少的假设 NAA衍生的醋酸酯在脂肪酸/脂肪合成中的有效性 髓鞘形成。制作CD的动物模型涉及产生杂合子 以及ASPA基因被敲除的纯合子小鼠。光盘的发展 将使用行为测试和随后的光和电子来确认 对大脑的显微分析。上面提到的假设是 在动物模型中进行测试,以确定是否使用 醋酸盐是一种很容易进入大脑的脂肪酸前体,它可以防止 CD在动物模型中的发展。基于内源性和无毒 醋酸盐的性质,以及治疗Cd,醋酸盐的紧迫性 在正常小鼠中,给药将在剂量和 安全,以使醋酸盐尽快进行临床试验。朝向这些 目的利用聚合酶链式反应成功克隆并表达小鼠ASPA基因。 策略,并已鉴定出一种人工细菌染色体,含有 完整的ASPA基因。基因组克隆的测序正在进行中。成功 拟议的研究完成后,将确定将醋酸盐用于 CD的治疗。此外,拟议研究的方法创新 将通过刺激对神经的研究而在该领域产生重大影响 NAA和N-乙酰天冬氨酸谷氨酸的系统特异性作用 来自NAA的神经递质。

项目成果

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ARYAN Mangalam NAMBOODIRI其他文献

ARYAN Mangalam NAMBOODIRI的其他文献

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{{ truncateString('ARYAN Mangalam NAMBOODIRI', 18)}}的其他基金

Acetate Supplementation as a therapeutic strategy for Canavan disease
补充乙酸作为卡纳万病的治疗策略
  • 批准号:
    8803820
  • 财政年份:
    2014
  • 资助金额:
    $ 18.53万
  • 项目类别:
Acetate Supplementation as a therapeutic strategy for Canavan disease
补充乙酸作为卡纳万病的治疗策略
  • 批准号:
    8700038
  • 财政年份:
    2014
  • 资助金额:
    $ 18.53万
  • 项目类别:
Intranasal CNS delivery of drugs against organophosphorous threat agents
鼻内中枢神经系统输送针对有机磷威胁物质的药物
  • 批准号:
    8417465
  • 财政年份:
    2012
  • 资助金额:
    $ 18.53万
  • 项目类别:
Intranasal CNS delivery of drugs against organophosphorous threat agents
鼻内中枢神经系统输送针对有机磷威胁物质的药物
  • 批准号:
    8551756
  • 财政年份:
    2012
  • 资助金额:
    $ 18.53万
  • 项目类别:
Biosynthesis of N-acetylaspartate
N-乙酰天冬氨酸的生物合成
  • 批准号:
    6867819
  • 财政年份:
    2004
  • 资助金额:
    $ 18.53万
  • 项目类别:
Biosynthesis of N-acetylaspartate
N-乙酰天冬氨酸的生物合成
  • 批准号:
    6954209
  • 财政年份:
    2004
  • 资助金额:
    $ 18.53万
  • 项目类别:
CANAVAN DISEASE PATHOGENESIS AND TREATMENT
卡纳万病的发病机制和治疗
  • 批准号:
    6529581
  • 财政年份:
    2000
  • 资助金额:
    $ 18.53万
  • 项目类别:
CANAVAN DISEASE PATHOGENESIS AND TREATMENT
卡纳万病的发病机制和治疗
  • 批准号:
    6194409
  • 财政年份:
    2000
  • 资助金额:
    $ 18.53万
  • 项目类别:
Canavan Disease: Pathogenesis and Treatment
卡纳万病:发病机制和治疗
  • 批准号:
    7415290
  • 财政年份:
    1999
  • 资助金额:
    $ 18.53万
  • 项目类别:
Canavan Disease: Pathogenesis and Treatment
卡纳万病:发病机制和治疗
  • 批准号:
    7656990
  • 财政年份:
    1999
  • 资助金额:
    $ 18.53万
  • 项目类别:

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STRUCTURAL STUDIES OF ANTITUMOR AMIDOHYDROLASES
抗肿瘤酰胺水解酶的结构研究
  • 批准号:
    3171525
  • 财政年份:
    1983
  • 资助金额:
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