Stress Granules and the Biology of TDP-43

应激颗粒和 TDP-43 的生物学

基本信息

批准号：
8625475
负责人：
Benjamin L Wolozin
金额：
$ 41.98万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8625475
关键词：
Accounting Alanine Amyotrophic Lateral Sclerosis Aryl Hydrocarbon Receptor Biochemical Biology C9ORF72 Cessation of life Chemicals Clinic Code Cytoplasmic Granules DNA Development Disease Disease Progression Familial Amyotrophic Lateral Sclerosis Functional disorder Funding Gene Expression Gene Proteins Gene Targeting Genes Genetic Genetic Risk Genetic Transcription Genomics Genotype Hematopoiesis Length Libraries Ligands Link Lymphocyte Malignant Neoplasms Measures Mediating Motor Neurons Mutate Mutation National Institute of Environmental Health Sciences Neurites Neurons Organophosphates Outcome Pathology Patients Phenotype Principal Investigator Process Proteins RNA Regulation Reporter Research Research Personnel Research Project Grants Risk Role Sampling Sequence Analysis Source Stress Testing Toxic Environmental Substances Variant activating transcription factor aryl hydrocarbons cohort environmental chemical gene discovery gene environment interaction genetic analysis genetic linkage genetic variant induced pluripotent stem cell inhibitor/antagonist innovation link protein lipid biosynthesis mutant neurotoxic neurotoxicity novel programs protein TDP-43 protein aggregation protein expression public health relevance research study response risk variant small hairpin RNA toxicant

项目摘要

The major objectives of this ViCTER program are to test novel mechanisms of gene-environment interactions. We will test whether environmental toxicants linked to amyotrophic lateral sclerosis (ALS) act in part through genes linked to ALS, including the newly discovered gene, C9ORF72, as well as the gene PON2, which biotransforms environmental toxicants. We will also test whether toxicants might contribute to ALS by acting through the aryl hydrocarbon (AhR) receptor, which is known to mediate toxicant action in other diseases, such as cancers. Hexanucleotide expansions in C9ORF72 account for 30% of cases of familial ALS. Inclusion of samples from ALS patients through our co-investigator, Dr. Rademakers, allows us to generate iPSCs from subjects with these mutations. The AhR is a ligand- activated transcription factor that mediates many of the effects of environmental toxicants in hematopoiesis, lymphocyte development, adipogenesis and cancer. We hypothesize that AhR ligands and other environmental chemicals, many of which are neurotoxic might also increase the risk of ALS by stimulating transcription of genes linked to ALS. The experiments in this consortium could identify novel mechanisms through which environmental toxicants might contribute to ALS. In addition, the availability of novel, non-toxic AhR antagonists, which were generated by Dr. Sherr's team, offers the exciting prospect of potentially inhibiting the expression of genes linked to ALS, a strategy that might reduce or delay the pathophysiology of ALS. Aim 1 will determine the role of AhR and PON2 genetic variants in ALS using the Mayo ALS cohort; Dr. Rademakers will perform in-depth genetic analyses of AhR in ~750 ALS patients and matched controls ascertained at Mayo Clinic to determine whether there are common genetic risk variants and/or rare modifier variants or disease causing variants in AhR. In Aim 2, Dr. Murphy will generate iPSC lines from subjects identified by Dr. Rademakers who have ALS and express mutated C9ORF72 and PON2. In Aim 3, Dr. Wolozin will determine whether genes linked to ALS (e.g., TARDBP, C9ORF72 or PON2) increase the vulnerability and/or pathology in response to ALS-linked environmental toxicants in MN iPSCs. Toxicants linked to ALS will be utilized, including ¿- methyl amino alanine, neurotoxic organophosphates and environmental AhR ligands. In Aim 4, Dr. Sherr will determine whether AhR ligands increase the expression of ALS-linked genes and proteins, and modify the resulting phenotypes. He will use AhR-specific shRNA, novel inhibitors, qPCR and AhR-reporter-transduced iPSCs to characterize AhR expression and activity in MN iPSCs. Thus, in this consortium, we will determine if AhR contributes to ALS through regulation of ALS-associated genes, and whether such activation modifies the pathophysiology of genes or proteins linked to ALS.

这个Victer计划的主要目标是测试基因环境的新机制互动。我们将测试环境有毒物质是否与肌萎缩性侧面硬化症有关（ALS）部分通过与ALS相关的基因作用，包括新发现的基因C9orf72以及基因PON2，生物转化具有环境毒性。我们还将测试是否有毒通过通过芳基烃（AHR）受体作用来促进ALS，该受体已知会介导在其他疾病（例如癌症）中的有毒作用。 C9ORF72中的六核苷酸扩展家庭ALS病例中有30％。通过我们的共同评估器Dr.包括ALS患者的样品 Rademaker，允许我们从具有这些突变的受试者中生成IPSC。 AHR是配体 - 激活的转录因子介导了环境有毒物质在造血，淋巴细胞发育，脂肪生成和癌症。我们假设AHR配体和其他环境化学物质（其中许多是神经毒性）也可能增加ALS的风险通过刺激与ALS相关的基因的转录。该财团中的实验可以识别环境有毒物质可能对ALS贡献的新型机制。另外，由Sherr博士的团队产生的新颖的无毒AHR拮抗剂的可用性可能抑制与ALS相关的基因表达的令人兴奋的前景，该策略可能减少或延迟ALS的病理生理。 AIM 1将确定AHR和PON2通用的作用使用Mayo ALS队列中ALS中的变体； Rademakers博士将对〜750名ALS患者的AHR并在Mayo诊所确定的对照组匹配，以确定是否在那里是常见的遗传风险变异和/或稀有修饰剂变体或疾病，导致AHR变异。在 AIM 2，Murphy博士将从具有ALS的Rademakers确定的主题中生成IPSC线条并表示突变的C9orf72和PON2。在AIM 3中，Wolozin博士将确定基因是否联系在一起到ALS（例如TARDBP，C9ORF72或PON2）增加脆弱性和/或病理，以应对 MN IPSC中ALS连接的环境有毒物质。将利用与ALS相关的有毒物质，包括 - 甲基氨基丙氨酸，神经毒性有机磷酸盐和环境AHR配体。在AIM 4中，博士 Sherr将确定AHR配体是否增加了ALS连接基因和蛋白质的表达，并修改所得的表型。他将使用AHR特异性的shRNA，新型抑制剂，QPCR和 AHR重复蛋白转移的IPSC表征Mn IPSC中的AHR表达和活性。那，这是财团，我们将确定AHR是否通过调节ALS相关基因的调节为ALS贡献这种激活是否改变了与ALS相关的基因或蛋白质的病理生理。