Treatment of CBS Deficiency with Proteostasis Modulators

用蛋白质稳态调节剂治疗 CBS 缺乏症

基本信息

批准号：
9045611
负责人：
WARREN D KRUGER
金额：
$ 39.72万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9045611
关键词：
Adult Affect Alleles Amino Acids Animals Back Cells Clinic Clinical Complex Cystathionine beta-Synthase Data Data Set Disease Drug usage Effectiveness Environment Genes Goals Health Hereditary Disease Homocysteine Homocystine Human Inborn Errors of Metabolism Incidence Individual Lead Marketing Mental Retardation Metabolism Methionine Methodology Missense Mutation Modeling Molecular Chaperones Molecular Conformation Mus Mutation Osteoporosis Other Genetics Pathway interactions Patients Pharmaceutical Preparations Phenotype Plasma Process Proteins Recycling Staging System Testing Thrombosis Translating Ubiquitin Variant Work dietary restriction drug testing enzyme activity functional restoration humanized mouse in vivo insight lens mouse model multicatalytic endopeptidase complex mutant novel novel strategies polypeptide protein folding research study treatment strategy vitamin therapy

项目摘要

DESCRIPTION (provided by applicant): Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of cellular metabolism. Homocysteine is an intermediary metabolite derived from methionine. It can either be recycled back to methionine, or shunted down the transsulfuration pathway by the action of cystathionine beta-synthase (CBS). Individuals with mutations in CBS have clinical CBS deficiency, characterized by extreme elevations in plasma total homocysteine (tHcy) and phenotypes including increased incidence of thrombosis, osteoporosis, dislocated lenses, and mental retardation. Current treatment strategies involve dietary restriction and vitamin therapy, but these are only partially effective and do not work in all patients. Over 85% of the described mutations in CBS deficient patients are missense mutations in which a single incorrect amino acid is substituted into the CBS polypeptide. These mutations are believed to effect enzymatic activity because the mutant protein fails to assemble into an active conformation. The ability of a protein to achieve an activ conformation is affected by a variety of intracellular protein networks including the chaperone system and the ubiquitin/proteasome system, collectively referred to as the proteostasis network. Proteostasis modulators are drugs that perturb various aspects of these networks. The preliminary data, shows that it is possible to stimulate proper folding of different mutant human CBS alleles expressed in mice by proteostasis modulating drugs. The overall goal of this proposal is to explore the interactions between proteostasis modulators and mutant alleles of CBS in a mouse model of CBS deficiency. There are three specific aims: (1) Generate and characterize new mouse models of CBS deficiency (2) Test four known proteostasis modulators for effectiveness of rescue in vivo and (3) Mechanistic studies of how proteostasis modulators effect the intracellular chaperone environment. If successful, the experiments described here could lead to novel treatments for CBS deficiency and potentially other genetic diseases associated with missense mutations.

描述（由申请人提供）：新陈代谢的先天错误包括涉及细胞代谢疾病的大量遗传疾病。同型半胱氨酸是一种衍生自蛋氨酸的中介代谢物。可以将其回收回蛋氨酸，也可以通过胱淀粉β-合酶（CBS）的作用将转移途径降低。 CBS中突变的个体具有临床CBS缺乏症，其特征是血浆总同型半胱氨酸（THCY）的极端升高和表型，包括增加血栓形成，骨质疏松症，骨质疏松，脱位透镜和智力低下的发病率。当前的治疗策略涉及饮食限制和维生素疗法，但这些策略仅部分有效，并且在所有患者中都不起作用。在CBS缺乏的患者中，超过85％的描述突变是错义突变，其中将单个不正确的氨基酸取代为CBS多肽。这些突变被认为会产生酶活性，因为突变蛋白无法组装成活性构象。蛋白质实现活性构象的能力受到各种细胞内蛋白质网络的影响，包括伴侣系统和泛素/蛋白酶体系统，共同称为蛋白质的网络。蛋白质调节剂是扰动这些网络各个方面的药物。初步数据表明，可以通过调节药物来刺激小鼠在小鼠中表达的不同突变的人CBS等位基因的适当折叠。该提案的总体目标是探索CBS缺乏症小鼠模型中CBS的蛋白质调节剂与突变等位基因之间的相互作用。有三个特定的目的：（1）生成和表征CBS缺乏症的新小鼠模型（2）测试四个已知的蛋白质抑制剂调节剂，以在体内拯救的有效性以及（3）蛋白质量调节剂如何影响细胞内伴侣环境的机理研究。如果成功，此处描述的实验可能会导致对CBS缺乏症的新治疗方法以及与错义突变有关的其他遗传疾病。