CANAVAN DISEASE PATHOGENESIS AND TREATMENT

卡纳万病的发病机制和治疗

• 批准号: 6529581
• 负责人: ARYAN Mangalam NAMBOODIRI
• 金额: $ 18.53万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-20 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6529581
• 关键词: acetates; amidohydrolases; aspartate; autosomal recessive trait; behavior test; cerebral degeneration; congenital brain disorder; disease /disorder model; electron microscopy; enzyme deficiency; gene targeting; laboratory mouse; lipid biosynthesis; model design /development; molecular cloning; myelinopathy; pathologic process

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（改编自申请人的摘要）：卡纳万病（CD）是一种 出生后发展的常染色体隐性神经退行性疾病， 通常在10岁前死亡。CD在世界各地都有，但大多数 到目前为止，已经确定的患者中有10%是德系犹太人后裔。CD载体 该人群中的频率估计为1/38，高达 Tay Sachs病CD是由编码CD的基因突变引起的。 N-乙酰天冬氨酸（NAA）是一种高度降解N-乙酰天冬氨酸（NAA）的酶， 丰富的（5-10 mM）和神经系统特异性代谢物，转化为乙酸盐， 天冬氨酸。然而，无论是CD的发病机制还是NAA的功能， 已被定义。此外，没有用于探索潜力的动物模型 CD的治疗是可行的。研究者们提议制作一个老鼠模型 并测试CD发病机制涉及减少的假设 NAA衍生的乙酸盐用于脂肪酸/脂质合成的可用性 髓鞘形成制作CD的动物模型涉及产生杂合的 以及ASPA基因被敲除的纯合子小鼠。CD的发展 将通过行为测试和随后的光和电子测试来证实 大脑的显微镜分析上述假设将是 在动物模型中通过确定是否用 醋酸盐是一种脂肪酸前体，很容易进入大脑， 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的紧迫性，醋酸盐 将在正常小鼠中优化给药的剂量， 尽快开展醋酸盐的临床试验。对这些 目的，他们已经成功地克隆和表达小鼠ASPA cDNA的PCR 战略，并确定了一个人工细菌染色体含有 ASPA基因。基因组克隆测序正在进行中。成功 完成拟议的研究将确定醋酸盐的用途， 治疗CD。此外，拟议研究的方法创新 将对该领域产生重大影响， NAA和N-乙酰基谷氨酸的系统特异性作用， 来源于NAA的神经递质。

项目成果

Mutational analysis of aspartoacylase: implications for Canavan disease.

天冬氨酸酰化酶的突变分析：对卡纳万病的影响。

• DOI: 10.1016/j.brainres.2007.02.069
• 发表时间: 2007
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Hershfield,JeremyR;Pattabiraman,Nagarajan;Madhavarao,ChikkathurN;Namboodiri,MAAryan
• 通讯作者: Namboodiri,MAAryan

Defective myelin lipid synthesis as a pathogenic mechanism of Canavan disease.

髓磷脂脂质合成缺陷是卡纳万病的致病机制。

• DOI: 10.1007/0-387-30172-0_10
• 发表时间: 2006
• 期刊: Advances in experimental medicine and biology
• 作者: Namboodiri,AryanMA;Moffett,JohnR;Arun,Peethambaran;Mathew,Raji;Namboodiri,Sreela;Potti,Asha;Hershfield,Jeremy;Kirmani,Batool;Jacobowitz,DavidM;Madhavarao,ChikkathurN
• 通讯作者: Madhavarao,ChikkathurN

A radiometric assay for aspartoacylase activity in cultured oligodendrocytes.

培养少突胶质细胞中天冬氨酸酰化酶活性的放射测定。

• DOI: 10.1016/s0003-2697(02)00225-7
• 发表时间: 2002
• 期刊: Analytical biochemistry
• 影响因子: 2.9
• 作者: Madhavarao,CN;Hammer,JA;Quarles,RH;Namboodiri,MAA
• 通讯作者: Namboodiri,MAA

NAA synthesis and functional roles.

NAA 合成和功能作用。

• DOI: 10.1007/0-387-30172-0_4
• 发表时间: 2006
• 期刊: Advances in experimental medicine and biology
• 作者: Madhavarao,ChikkathurN;Namboodiri,AryanMA
• 通讯作者: Namboodiri,AryanMA