Molecular Pathogenesis and Treatment of MNGIE

MNGIE 的分子发病机制和治疗

基本信息

批准号：
8053754
负责人：
MICHIO HIRANO
金额：
$ 40.01万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8053754
关键词：
Age Aging Allogeneic Bone Marrow Transplantation Allogenic Animals Biochemical Blood Bone Marrow Transplantation Brain Cachexia Cell Culture Techniques Cells Childhood Clinical Defect Deoxyuridine Disease Drug Kinetics Encapsulated Enzymes Genes Genetic Materials Hematopoietic stem cells Hereditary Disease Human In Vitro Knock-out Knockout Mice Lead Leukoencephalopathy Mitochondria Mitochondrial DNA Molecular Molecular Genetics Monitor Mus Muscle Weakness Mutation Neurodegenerative Disorders Nevada Nucleosides Nucleotides Ophthalmoplegia Outcome Outcome Measure Pathogenesis Patients Peripheral Nervous System Diseases Phenotype Plasma Point Mutation Ptosis Pyrimidine Nucleosides Reporting Research Personnel Respiratory Chain Role Site Stem cell transplant Stress Testing Therapeutic Thymidine Thymidine Phosphorylase Tissues Transplantation Treatment Efficacy Universities Uridine Phosphorylase base disease-causing mutation emerging adult enzyme replacement therapy gastrointestinal genetic linkage human disease insight motility disorder mouse model nanoparticle neuroimaging novel orbit muscle prevent primary outcome public health relevance research study restoration stem cell therapy

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a fatal autosomal recessive disease caused by mutations in the TYMP gene encoding thymidine phosphorylase (TP). The disease typically begins in childhood or early adulthood causes ptosis, ophthalmoplegia, severe gastrointestinal dysmotility leading to cachexia, peripheral neuropathy, leukoencephalopathy, and alterations of mitochondrial DNA (mtDNA). Most patients die by age 40. Through genetic linkage studies, we identified the causative gene and demonstrated that TYMP mutations cause TP deficiency, which leads to dramatic elevations of thymidine and deoxyuridine in plasma and tissues of patients. In addition, we identified multiple deletions, depletion, and site-specific point mutations of mtDNA in patients' tissues and cells. Based on these findings, we hypothesize that toxic accumulations of thymidine and deoxyuridine nucleosides cause imbalances of mitochondrial deoxynucleotide pools leading to mtDNA instability. Other investigators have demonstrated that TP-expressing human cells cultured in high concentrations of thymidine have unbalanced mitochondrial nucleotide pools and develop partial depletion or multiple deletions of mtDNA. We have generated a TP and uridine phosphorylase (UP) double-knockout (TP-/-UP-/-) mouse model of MNGIE. The TP-/-UP-/- mice show loss of TP activity, elevated levels of thymidine and deoxyuridine in tissues, mitochondrial nucleotide pool imbalances, and leukoencephalopathy with mtDNA depletion and respiratory chain defect. In this application, we propose to further test our hypotheses that: 1) TP deficiency causes toxic accumulation of thymidine, that, in turn, lead to nucleotide pool imbalances and mtDNA instability and 2) restoration of TP activity by bone marrow transplantation or nanoparticle enzyme replacement will be therapeutic. Three specific aims are proposed. Aim 1: TP-/-UP-/- mice will be administered thymidine to enhance the mitochondrial abnormalities. Aim 2: TP-/-UP-/- mice will undergo bone marrow transplantation before and after onset of leukoencephalopathy. Aim 3: TP encapulated in nanoparticles will be administered to TP-/-UP-/- mice. PUBLIC HEALTH RELEVANCE: Our studies of a rare and fatal genetic disease called MNGIE have revealed how a particular biochemical defects causes instability of genetic material in people. We propose to study a mouse model to understand and to treat this disorder. Studies of MNGIE may be relevant to a variety of human diseases, aging, comprehending stability of genetic material, and possibly neurodegenerative diseases.

描述（由申请人提供）：线粒体神经胃肠道脑瘤病（MNGIE）是一种致命的常染色体隐性疾病，是由编码胸苷磷酸酶（TP）的TYMP基因突变引起的。该疾病通常始于儿童时期或成年早期，导致眼科，严重的胃肠道不良运动障碍，导致卡赫西亚，周围神经病，白血病，白血病和线粒体DNA（mtdna）的改变。大多数患者在40岁时死亡。通过遗传连锁研究，我们确定了病因基因，并证明TYMP突变会导致TP缺乏症，从而导致胸苷和脱氧尿素在患者的血浆和组织中升高。此外，我们确定了患者组织和细胞中mtDNA的多个缺失，耗竭和特定点突变。基于这些发现，我们假设胸苷和脱氧尿苷核苷的毒性积累会导致线粒体脱氧核苷酸池的失衡，从而导致mtDNA不稳定。其他研究人员表明，表达TP的人类细胞在高浓度的胸苷中培养的人细胞具有不平衡的线粒体核苷酸池，并产生部分耗竭或MTDNA的多种缺失。我们已经生成了MNGIE的TP和尿苷磷酸化酶（UP）双敲击（TP - / - UP - / - ）模型。 TP - / - UP - / - 小鼠显示了TP活性的损失，组织中胸苷和脱氧尿酸的水平升高，线粒体核苷酸池失衡以及伴有mtDNA耗竭和呼吸道链缺损的白细胞病。在此应用中，我们建议进一步测试我们的假设：1）TP缺乏会导致胸苷的毒性积累，而胸苷池池失衡和mtDNA不稳定性以及2）通过骨髓移植或纳米粒子酶替代的恢复TP活性。提出了三个具体目标。 AIM 1：TP - / - UP - / - 小鼠将被施用胸苷以增强线粒体异常。 AIM 2：TP - / - UP - / - 小鼠将在白血病发作开始前后接受骨髓移植。 AIM 3：包裹在纳米颗粒中的TP将用于TP - / - UP - / - 小鼠。公共卫生相关性：我们对一种称为mngie的罕见和致命遗传疾病的研究揭示了特定的生化缺陷如何导致人们遗传物质的不稳定。我们建议研究小鼠模型以理解和治疗这种疾病。 MNGIE的研究可能与各种人类疾病有关，衰老，理解遗传物质的稳定性以及可能的神经退行性疾病。