Genetic Discovery and Pathobiology of Frontotemporal Lobar Degeneration and Related TDP-43 Proteinopathies

我们的研究项目旨在通过发现和后续研究与额颞叶变性（FTLD）和相关疾病相关的新疾病基因，为疾病发病机制提供新的见解，并确定新的治疗靶点。它的独特之处在于它跨越了从基因发现到治疗开发的疾病研究的全谱，这使得新的研究成果能够立即得到验证和应用。虽然近年来我们对FTLD的遗传学和影响额叶和颞叶大脑区域的神经退行性疾病的病理基础的理解取得了重大进展，但其诊断可能具有挑战性，并且没有减缓或阻止疾病进展的治疗方法，这凸显了FTLD患者巨大的未满足的医疗需求。FTLD占所有痴呆症的10-20%，具有重要的临床意义，因为与阿尔茨海默病（AD）相比，FTLD发病年龄更早，并且对人格、洞察力和语言沟通等核心人类品质产生巨大影响。FTLD最常见的病理亚型以TAR dna结合蛋白43 （FTLD- tdp）的病理聚集为特征，该蛋白也是肌萎缩侧索硬化症（ALS）患者的主要病理蛋白。作为我们研究计划的一部分，我们之前发现了前颗粒蛋白（GRN）突变和9号染色体开放阅读框72 （C9ORF72）基因的重复扩增，这是全球范围内FTLD-TDP的两个最常见原因。我们还发现跨膜蛋白106b基因（TMEM106B）是具有GRN和C9ORF72突变的FTLD个体疾病发病和/或表现的主要遗传修饰因子；但是，一定存在其他的致病基因和修饰因素。在这个研究项目中，我们将利用我们之前在该领域的贡献、新的资源和广泛的患者样本收集来识别新的FTLD致病基因和遗传修饰因子。一旦确定了新的基因，我们将利用R35机制提供的灵活性，立即开始功能研究，旨在加快将基因发现转化为患者的床边。通过发现新的FTLD疾病基因和更好地了解改变已知疾病基因（如GRN和C9ORF72）表达的因素，我们的研究项目将允许更准确和更早的诊断，为参与突变家庭遗传咨询的临床医生提供急需的指导，指导患者纳入未来的临床试验，并为FTLD病理生物学提供重要的新见解。我们的项目还将推进与疾病表型或进展相关的生物标志物的开发，并为治疗提供新的靶点。

Our Research Program aims to provide new insights into disease pathogenesis and to identify novel targets for therapy through the discovery and subsequent study of novel disease genes implicated in frontotemporal lobar degeneration (FTLD) and related disorders. It is unique in that it spans the full spectrum of disease research from gene discovery to therapy development, which allows immediate validation and application of novel research findings. While significant progress has been made in recent years to improve our understanding of the genetics of FTLD and the pathologies underlying this collection of neurodegenerative diseases affecting the frontal and temporal brain regions, its diagnosis can be challenging and no treatments to slow or stop disease progression exist, highlighting the enormous unmet medical need of FTLD patients. FTLD represents 10-20% of all dementias and is clinically important because of its earlier age at onset compared to Alzheimer's disease (AD) and its dramatic impact on core human qualities, including personality, insight and verbal communication. The most common pathological subtype of FTLD is characterized by pathological aggregates of the TAR DNA-binding protein 43 (FTLD-TDP), which is also the main pathological protein in patients with amyotrophic lateral sclerosis (ALS). As part of our Research Program we previously identified mutations in progranulin (GRN) and repeat expansions in the chromosome 9 open reading frame 72 (C9ORF72) gene, the two most common causes of FTLD-TDP world-wide. We also identified the transmembrane protein 106 B gene (TMEM106B) as a major genetic modifier of disease onset and/or presentation in FTLD individuals with GRN and C9ORF72 mutations; however, other causal genes and modifying factors must exist. In this Research Program we will leverage our previous contributions to the field, novel resources and an extensive collection of patient samples to identify novel causal FTLD genes and genetic modifiers. Once new genes are identified, we will capitalize on the flexibility afforded by the R35 mechanism to immediately begin functional studies designed to expedite the translation of genetic discoveries to the patient's bedside. Through the discovery of novel FTLD disease genes and a better understanding of the factors that modify the expression of known disease genes such as GRN and C9ORF72, our Research Program will allow more accurate and earlier diagnosis, provide much needed guidance for clinicians involved in genetic counseling of mutation families, guide the inclusion of patients for future clinical trials and provide important novel insight into FTLD pathobiology. Our Program will also advance the development of biomarkers associated with disease phenotype or progression and provide novel targets for therapies.