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

项目摘要/摘要 肌萎缩侧索硬化症(ALS)及相关疾病患者中存在显著的表型变异 疾病，如额颞叶痴呆(FTD)、原发性侧索硬化症(PLS)、进行性肌肉 萎缩症(PMA)和遗传性痉挛截瘫(HSP)，与年龄和发病部位有关 与低运动神经元病理、认知功能障碍的存在和程度、发病率 疾病发生后的进展和生存。为了探索这种异质性，我们将研究一口井- 在Create Consortium的表型-基因-生物标记物(PGB)中登记的患者的特征队列 我们已经为他收集了大量的临床和基因组数据。我们的目标是识别基因变异 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、发病后存活率)。我们的战略将包括创新 方法(例如，逆转录病毒插入和病毒整合的检测)和尖端技术(长时间 阅读单分子实时[SMRT]测序)，以发现迄今错过的变异。 此外，我们将以有针对性的方式探索基因与环境的相互作用，重点是 蛋白质折叠和DNA修复途径以及环境风险因素(如吸烟)。复制将 通过我们庞大的协作网络进行研究。我们通过研究确定的因素将是 提高我们破译这类疾病表型异质性的基础的能力，这将是至关重要的 为未来临床试验的成功干杯。

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.