High-Throughput Genomic Approaches to Identify ALS Genes

鉴定 ALS 基因的高通量基因组方法

• 批准号: 7538340
• 负责人: Robert H. Brown
• 金额: $ 50.99万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2011-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7538340
• 关键词: Accounting; Affect; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animals; Bacterial Artificial Chromosomes; Base Pairing; Candidate Disease Gene; Cell Death; Cell model; Chromosomes; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 9; Classification; Critical Pathways; DNA; Degenerative Disorder; Disease; Disease Association; Drug Design; Engineering; Exons; Family; Functional RNA; Functional disorder; Gene Mutation; Generations; Genes; Genomics; Goals; Haploidy; Human; Hybrid Cells; Individual; Inherited; Knock-in Mouse; Libraries; Link; Maps; Methodology; Methods; Microinjections; Modeling; Molecular; Motor Neuron Disease; Motor Neurons; Mus; Mutation; Neurodegenerative Disorders; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; SOD1 gene; Screening procedure; Therapeutic Intervention; Transgenic Mice; Variant; autosomal dominant trait; copper zinc superoxide dismutase; design; improved; insight; interest; mouse model; novel; research study; trait

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disorder of motor neurons. It is predominantly sporadic in occurrence, although 10% of cases are inherited as autosomal dominant traits. Mutations in the cytosolic copper-zinc superoxide dismutase gene (SOD1) account for 25% of dominantly-inherited cases. Considerable insight into the pathogenesis of both familial and sporadic ALS has been derived from studies of SOD 1 gene mutations. Several more dominantly-inherited ALS genes have been mapped but not yet identified. The goal of this project is to apply high-throughput genomic methodology systematically to identify novel ALS genes, and to develop new transgenic mouse models of ALS with these genes. These efforts will target the dominant ALS loci that we have recently identified on chromosomes 9, 16, and 20. The Specific Aims of this project are to: (1) Clone the disease loci from affected individuals with chromosome 9-, 16-, and 20- linked ALS in bacterial artificial chromosome (BAC) libraries prepared from mouse-human somatic cell hybrids haploid for the chromosomes of interest; (2) Screen candidate genes from the three ALS loci by exon sequencing; (3) Use high-through-put sequencing to determine the genomic sequence of the BAC contig spanning the ALS loci; (4) Confirm the disease association of candidate mutations; (5) Engineer mouse knock-in models of ALS by microinjection of BACs harboring mutations in the genes identified in Aims 1-4. Significance: These studies will be important because: (A) This project may serve as a new paradigm for the systematic identification of other Mendelian disease traits. (B) These studies will elucidate pathways critical for the survival of motor neurons. The same pathways may be involved in sporadic ALS. (C) An understanding of the molecular pathophysiology of this disease is essential to the rational design of therapeutic interventions. (D) The genes identified in these experiments can be used to create additional animal and cell models of ALS, allowing improved drug design and screening. (E) The characterization of cell death pathways in ALS may provide insights into mechanisms involved in other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases.

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）是运动神经元的致命退行性疾病。尽管有10％的病例是常染色体显性特征，但它主要是零星的。胞质铜锌超氧化物歧化酶基因（SOD1）中的突变占主要结构病例的25％。对家族性和零星ALS的发病机理的洞察力已有很大的见解来自SOD 1基因突变的研究。已经映射了几个更重要的ALS基因，但尚未确定。该项目的目的是系统地应用高通量基因组方法，以识别新型ALS基因，并使用这些基因开发新的ALS的转基因小鼠模型。这些努力将针对我们最近在染色体9、16和20上确定的主要ALS基因座。该项目的具体目的是：（1）克隆疾病基因座的疾病基因座，这些疾病基因座是9-，16和20连接的染色体ALS在细菌染色体（BAC）库中的染色体Als（BAC）中的染色体（BAC）库中，该图书馆（BAC）来自小鼠型小细胞杂种的兴趣，这些疾病是小鼠杂种杂种杂种杂种杂种杂种的杂种。 （2）通过外显子测序来自三个ALS基因座的筛选候选基因； （3）使用高通道测序来确定跨越ALS基因座的BAC重叠群的基因组序列； （4）确认候选突变的疾病协会； （5）通过对AIMS 1-4中鉴定的基因中携带突变的BAC进行显微注射，工程师小鼠敲入ALS的模型。意义：这些研究将很重要，因为：（a）该项目可能是对其他孟德尔疾病特征进行系统鉴定的新范式。 （b）这些研究将阐明对运动神经元存活至关重要的途径。同样的途径可能涉及零星的ALS。 （c）了解该疾病的分子病理生理学对于治疗干预措施的合理设计至关重要。 （d）这些实验中鉴定的基因可用于创建ALS的其他动物和细胞模型，从而改善了药物设计和筛查。 （e）ALS中细胞死亡途径的表征可以提供对其他神经退行性疾病（例如阿尔茨海默氏病和帕金森氏病）涉及的机制的见解。

项目成果

Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis.

• DOI: 10.1001/jamaneurol.2016.1114
• 发表时间: 2016-07-01
• 期刊: JAMA neurology
• 影响因子: 29
• 作者: Fogh I;Lin K;Tiloca C;Rooney J;Gellera C;Diekstra FP;Ratti A;Shatunov A;van Es MA;Proitsi P;Jones A;Sproviero W;Chiò A;McLaughlin RL;Sorarù G;Corrado L;Stahl D;Del Bo R;Cereda C;Castellotti B;Glass JD;Newhouse S;Dobson R;Smith BN;Topp S;van Rheenen W;Meininger V;Melki J;Morrison KE;Shaw PJ;Leigh PN;Andersen PM;Comi GP;Ticozzi N;Mazzini L;D'Alfonso S;Traynor BJ;Van Damme P;Robberecht W;Brown RH;Landers JE;Hardiman O;Lewis CM;van den Berg LH;Shaw CE;Veldink JH;Silani V;Al-Chalabi A;Powell J
• 通讯作者: Powell J

Serum ferritin and metal levels as risk factors for amyotrophic lateral sclerosis.

• DOI: 10.2174/1874205x00802010051
• 发表时间: 2008-09-12
• 期刊: The open neurology journal
• 作者: Qureshi, Muddasir;Brown, Robert H Jr;Rogers, Jack T;Cudkowicz, Merit E
• 通讯作者: Cudkowicz, Merit E

Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1.

• DOI: 10.1016/j.stem.2014.03.004
• 发表时间: 2014-06-05
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Kiskinis E;Sandoe J;Williams LA;Boulting GL;Moccia R;Wainger BJ;Han S;Peng T;Thams S;Mikkilineni S;Mellin C;Merkle FT;Davis-Dusenbery BN;Ziller M;Oakley D;Ichida J;Di Costanzo S;Atwater N;Maeder ML;Goodwin MJ;Nemesh J;Handsaker RE;Paull D;Noggle S;McCarroll SA;Joung JK;Woolf CJ;Brown RH;Eggan K
• 通讯作者: Eggan K

Mitochondrial DNA variations in Madras motor neuron disease.

马德拉斯运动神经元疾病中的线粒体 DNA 变异。

• DOI: 10.1016/j.mito.2013.02.003
• 发表时间: 2013
• 期刊: Mitochondrion
• 影响因子: 4.4
• 作者: Govindaraj,Periyasamy;Nalini,Atchayaram;Krishna,Nithin;Sharath,Anugula;Khan,NahidAkhtar;Tamang,Rakesh;Gourie-Devi,M;Brown,RobertH;Thangaraj,Kumarasamy
• 通讯作者: Thangaraj,Kumarasamy

Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis.

• DOI: 10.1038/nature11280
• 发表时间: 2012-08-23
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Wu, Chi-Hong;Fallini, Claudia;Ticozzi, Nicola;Keagle, Pamela J.;Sapp, Peter C.;Piotrowska, Katarzyna;Lowe, Patrick;Koppers, Max;McKenna-Yasek, Diane;Baron, Desiree M.;Kost, Jason E.;Gonzalez-Perez, Paloma;Fox, Andrew D.;Adams, Jenni;Taroni, Franco;Tiloca, Cinzia;Leclerc, Ashley Lyn;Chafe, Shawn C.;Mangroo, Dev;Moore, Melissa J.;Zitzewitz, Jill A.;Xu, Zuo-Shang;van den Berg, Leonard H.;Glass, Jonathan D.;Siciliano, Gabriele;Cirulli, Elizabeth T.;Goldstein, David B.;Salachas, Francois;Meininger, Vincent;Rossoll, Wilfried;Ratti, Antonia;Gellera, Cinzia;Bosco, Daryl A.;Bassell, Gary J.;Silani, Vincenzo;Drory, Vivian E.;Brown, Robert H., Jr.;Landers, John E.
• 通讯作者: Landers, John E.