Genes and Genetic Models in Motor Neuron Disorders

运动神经元疾病的基因和遗传模型

基本信息

批准号：
7253114
负责人：
TEEPU SIDDIQUE
金额：
$ 34.55万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7253114
关键词：
15q15 2q33 9q21-q22 Adolescent Affect Amyotrophic Lateral Sclerosis Animal Model Animals Behavior Binding Binding Proteins Bioinformatics Breeding Chromosomes Code Dementia Development Disease Drug Formulations Familial Amyotrophic Lateral Sclerosis Fluorescence Microscopy Fluorescence Resonance Energy Transfer Future Genes Genetic Genetic Models Goals Hereditary Spastic Paraparesis Hereditary Spastic Paraplegia Human Immunoprecipitation Inherited Intervention Investigation Knock-out Label Laboratories Lead Link Mammalian Cell Modeling Modification Molecular Molecular Diagnosis Motor Motor Neurons Mus Mutate Mutation Pathogenesis Pathology Pathway interactions Phenotype Prevention strategy Primary Lateral Sclerosis Protein Overexpression Proteins Resources Role Signal Pathway System Techniques Testing Therapeutic Transgenic Organisms Work X Chromosome base clinical phenotype design gain of function mutation gene discovery knockout animal loss of function motor neuron degeneration mouse model mutant novel prevent programs protein protein interaction research study spastin success yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Familial amyotrophic lateral sclerosis (FALS), 'pure' hereditary spastic paraparesis (HSP) and primary lateral sclerosis (PLS) are genetically heterogeneous disorders caused by motor neuron degeneration. These disorders either affect, both the upper and lower motor neurons (FALS), or primarily the upper motor neuron (HSP and PLS). The long-term goal of my laboratory is to identify the genetic contribution to the pathogenesis of these disorders. Success in this goal will lead to the formulation of interventions based on disease mechanisms to prevent, postpone and treat these and related disorders. We now plan to build on the work we accomplished in the last five years as part of a program project (NS 21442). We fulfilled all the Specific Aims such that we identified the ALSIN gene, that cause both recessive FALS (ALS2) and recessive juvenile PLS (JPLS1), on chromosome 2q33, studied mutations in SPASTIN that cause HSP (SPG5), and identified new loci for dominant ALS (on the X-chromosome) and ALS/dementia on chromosome 9q21-q22. We will further expand our gene discovery effort in recessive ALS and recessive HSP develop genetic models of FALS, JPLS, and HSP, and interrogate the products of causative genes for their protein-protein interactions to trace their signaling pathways. We plan to accomplish these goals by three main Specific Aims (1) Identify the genes for a more common form of recessive FALS (ALS5) on chromosome 15q15-q21 and a common form of recessive HSP (SPG5A) on chromosome 8q. (2) Develop genetic models of alsin for the JPLS and ALS phenotypes and of spastin for the HSP phenotype (SPG4). (3) Identify protein interactions of alsin. In the previous period we narrowed the loci for ALS5 and SPG5A. We will use high throughput sequencing and bioinformatic support to identify these genes, as we successfully did the case of the ALS2 gene. We will make knockout models for alsin and spastin, to study the pathology and pathogenesis of these disorders. Finally, the interacting partner proteins of alsin and subsequently of spastin will be interrogated by the two-hybrid systems and immunoprecipitation. Interaction will be confirmed by dual labeled confocal microscopy and FRET analysis.

描述（由申请人提供）：家族性肌萎缩侧索硬化症（FALS）、“纯”遗传性痉挛性截瘫（HSP）和原发性侧索硬化症（PLS）是由运动神经元变性引起的遗传异质性疾病。这些疾病要么影响上运动神经元和下运动神经元 (FALS)，要么主要影响上运动神经元（HSP 和 PLS）。我实验室的长期目标是确定遗传对这些疾病发病机制的贡献。这一目标的成功将导致根据疾病机制制定干预措施，以预防、推迟和治疗这些疾病及相关疾病。我们现在计划在过去五年中作为计划项目 (NS 21442) 的一部分完成的工作的基础上继续发展。我们实现了所有具体目标，例如我们在染色体 2q33 上鉴定了导致隐性 FALS (ALS2) 和隐性幼年 PLS (JPLS1) 的 ALSIN 基因，研究了导致 HSP (SPG5) 的 SPASTIN 突变，并鉴定了新的位点显性 ALS（X 染色体上）和染色体 9q21-q22 上的 ALS/痴呆。我们将进一步扩大隐性ALS和隐性HSP的基因发现工作，开发FALS、JPLS和HSP的遗传模型，并询问致病基因产物的蛋白质-蛋白质相互作用，以追踪其信号通路。我们计划通过三个主要具体目标来实现这些目标 (1) 识别 15q15-q21 染色体上更常见的隐性 FALS (ALS5) 形式和 8q 染色体上的常见隐性 HSP (SPG5A) 形式的基因。 (2) 开发用于 JPLS 和 ALS 表型的 alsin 遗传模型以及用于 HSP 表型 (SPG4) 的 spastin 遗传模型。 (3) 鉴定alsin 的蛋白质相互作用。在上一时期，我们缩小了 ALS5 和 SPG5A 的基因座范围。我们将使用高通量测序和生物信息学支持来识别这些基因，就像我们成功地鉴定 ALS2 基因一样。我们将制作alsin和spastin的敲除模型，以研究这些疾病的病理学和发病机制。最后，alsin 和随后的 spastin 的相互作用伴侣蛋白将通过双杂交系统和免疫沉淀进行询问。相互作用将通过双标记共聚焦显微镜和 FRET 分析来确认。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effect of fluoxetine on disease progression in a mouse model of ALS.

DOI：
10.1152/jn.00425.2013
发表时间：
2014-06
期刊：
Journal of neurophysiology
影响因子：
2.5
作者：
Jenna E. Koschnitzky;K. Quinlan;T. Lukas;E. Kajtaz;Emily J Kocevar;W. Mayers;T. Siddique;C. Heckman
通讯作者：
Jenna E. Koschnitzky;K. Quinlan;T. Lukas;E. Kajtaz;Emily J Kocevar;W. Mayers;T. Siddique;C. Heckman

Intricacies of aetiology in intrafamilial degenerative disease.