Clinical Research in ALS & Related Disorders for Therapeutic Development (CReATe) - Project Core #2

项目总结/摘要 肌萎缩侧索硬化症（ALS）及相关疾病患者的表型差异显著， 疾病，例如额颞叶痴呆（FTD）、原发性侧索硬化（PLS）、进行性肌肉萎缩症（ALS）、 萎缩（PMA）和遗传性痉挛性截瘫（HSP），就年龄和疾病发作部位而言， 与下运动神经元病理学、认知功能障碍的存在和程度、疾病发生率 疾病发作后的进展和存活率。为了探索这种异质性，我们将研究一个良好的- 入组CReATe联盟表型-基因型-生物标志物（PGB）的患者特征队列 我们已经收集了大量的临床和基因组数据。我们的目标是识别遗传变异 改变ALS和相关疾病的潜在表型特征（发病年龄，快速与缓慢 疾病进展、认知障碍、从发病起的存活率）。我们的战略将包括创新 方法（例如，检测逆转录插入和病毒整合）和尖端技术（长- 读取单分子实时[SMRT]测序），以揭示迄今为止遗漏的变异。 此外，我们将通过关注基因的变异，有针对性地探索基因与环境的相互作用。 蛋白质折叠和DNA修复途径以及环境风险因素（例如，吸烟）。复制将 通过我们庞大的合作网络进行研究。我们通过研究确定的因素将 提高我们破译这组疾病表型异质性基础的能力， 未来临床试验的成功

Project Summary / Abstract There is marked phenotypic variability among patients with amyotrophic lateral sclerosis (ALS) and related disorders, such as frontotemporal dementia (FTD), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), and hereditary spastic paraplegia (HSP), with respect to age and site of disease onset, upper versus lower motor neuron pathology, presence and degree of cognitive dysfunction, rate of disease progression and survival from disease onset. To explore this heterogeneity, we will examine a well- characterized cohort of patients enrolled in the CReATe Consortium’s Phenotype-Genotype-Biomarker (PGB) Protocol, for whom we have collected a wealth of clinical and genomic data. We aim to identify genetic variants that modify underlying phenotypic characteristics of ALS and related diseases (age at onset, rapid versus slow disease progression, cognitive impairment, survival from onset). Our strategy will include innovative approaches (e.g., detection of retroelement insertion and viral integration) and cutting-edge technology (long- read single-molecule real-time [SMRT] sequencing) to uncover variation that has been missed thus far. Additionally, we will explore gene-environment interactions in a targeted manner by focusing on variants in protein folding and DNA repair pathways and environmental risk factors (e.g., cigarette smoking). Replication will be conducted in studies through our large collaborative network. The factors we identify through our studies will enhance our ability to decipher the basis for the phenotypic heterogeneity of this group of diseases and will be critical to the success of future clinical trials.