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Genetic modifiers of phosphoinositide mediated neurodegeneration

磷酸肌醇介导的神经变性的遗传修饰剂

基本信息

批准号：
8806880
负责人：
Guy Martin Lenk
金额：
$ 7.78万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2014-08-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8806880
关键词：
Adult Affect Age-Years Alleles Architecture Autophagocytosis Biology Cessation of life Charcot-Marie-Tooth Disease Collection Complex Congenic Strain Defect Development Disease Employee Strikes Epilepsy Exhibits Family Follow-Up Studies Future Gene Targeting Genes Genetic Genomics Genotype Goals Health Human Individual Inheritance Patterns Inherited Intervention Knockout Mice Laboratories Life Lipids Mediating Medicine Membrane Microgyria Modeling Mus Mutant Strains Mice Mutation Nerve Degeneration Nervous system structure Outcome Pathology Pathway interactions Patients Perinatal Peripheral Nervous System Diseases Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphotransferases Process Proteins Quantitative Trait Loci Scaffolding Protein Seizures Severities Severity of illness Signal Transduction Syndrome System Time Variant Work base congenic disease-causing mutation early childhood insight loss of function mouse model mutant nervous system disorder postnatal public health relevance therapeutic target trait

项目摘要

DESCRIPTION (provided by applicant): We are studying neurological disorders caused by deficiency of the signaling lipid PI(3,5)P2 (phosphatidylinositol-3,5-bisphosphate). PI(3,5)P2 is localized on membranes of the endolysosomal system. PI(3,5)P2 is generated by a complex including the kinase PIKFYVE, the scaffold protein VAC14, and the phosphatase FIG4 (Jin et al 2008). We demonstrated that mutations of FIG4 are responsible for the human neurological disorders Charcot-Marie-Tooth type 4J (CMT4J), Yunis-Varon syndrome, and polymicrogyria (Chow et al., 2007; Campeau et al., 2013; Baulac et al., 2014). Individuals with CMT4J and polymicrogyria exhibit variability in disease severity from early childhood to adulthood (Nicholson et al., 2011; Ben Cheikh BO et al., 2009). Variable severity is mimicked in mouse models with different strain backgrounds. Mice null for Fig4 and those homozygous for the Vac14 substitution L156R display early lethality on strain C57BL/6J but extended survival on strain C3HeB/FeJ. Our unique collection of mouse models of PI(3,5)P2 deficiency will be used to investigate this difference, using linkage and QTL analysis to elucidate the genetic architecture of the survival trait, to identify shared modifiers affecting survival of both Fig4 an Vac14 mutants. Future work will identify the responsible genes and target pathways for treatment of the human disorders.

描述（由申请人提供）：我们正在研究由信号脂质PI（3，5）P2（磷脂酰肌醇-3，5-二磷酸）缺乏引起的神经系统疾病。PI（3，5）P2定位于内溶酶体系统的膜上。PI（3，5）P2由包括激酶PIKFYVE、支架蛋白VAC 14和磷酸酶FIG 4的复合物产生（Jin等人2008）。我们证明了FIG 4的突变是人类神经系统疾病Charcot-Marie-Tooth 4J型（CMT 4J）、Yunis-Varon综合征和多小脑回症的原因（Chow et al.，2007; Campeau等人，2013; Baulac等人，2014年）。患有CMT 4J和多小脑回症的个体从儿童早期到成年表现出疾病严重程度的变化性（Nicholson et al.，2011年; Ben Cheetrich BO等人，2009年）。在具有不同品系背景的小鼠模型中模拟了不同的严重程度。图4无效的小鼠和Vac 14取代L156 R纯合的小鼠在菌株C57 BL/6 J上显示早期致死性，但在菌株C3 HeB/FeJ上延长存活。我们独特的PI（3，5）P2缺陷小鼠模型集合将用于研究这种差异，使用连锁和QTL分析来阐明存活性状的遗传结构，以鉴定影响Fig 4和Vac 14突变体存活的共有修饰物。未来的工作将确定负责基因和治疗人类疾病的靶向途径。