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

我们的研究计划旨在为疾病发病机制提供新的见解，并通过发现和后续研究涉及额颞叶变性（FTLD）和相关疾病的新疾病基因来确定新的治疗靶点。它的独特之处在于，它涵盖了从基因发现到治疗开发的疾病研究的全方位，允许立即验证和应用新的研究结果。虽然近年来已经取得了重大进展，以提高我们对FTLD遗传学的理解以及影响额叶和颞叶脑区域的神经退行性疾病的病理学基础，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存在，突出了FTLD患者巨大的未满足的医疗需求。FTLD占所有痴呆症的10-20%，并且由于其与阿尔茨海默病（AD）相比的早期发病年龄及其对核心人类素质（包括个性，洞察力和言语交流）的巨大影响而具有临床重要性。FTLD最常见的病理亚型的特征在于TAR DNA结合蛋白43（FTLD-TDP）的病理聚集体，其也是肌萎缩侧索硬化症（ALS）患者中的主要病理蛋白。 作为我们研究计划的一部分，我们以前确定了颗粒蛋白前体（GRN）突变和9号染色体开放阅读框72（C9 ORF 72）基因重复扩增，这是全球FTLD-TDP的两个最常见原因。我们还确定了跨膜蛋白106 B基因（TMEM 106 B）作为GRN和C9 ORF 72突变的FTLD个体中疾病发作和/或表现的主要遗传修饰因子;然而，必须存在其他致病基因和修饰因子。 在这项研究计划中，我们将利用我们以前对该领域的贡献，新资源和广泛收集的患者样本，以确定新的致病FTLD基因和遗传修饰剂。一旦新的基因被确定，我们将利用R35机制提供的灵活性，立即开始功能研究，旨在加快遗传发现的翻译到病人的床边。通过发现新的FTLD疾病基因和更好地了解修饰已知疾病基因（如GRN和C9 ORF 72）表达的因素，我们的研究计划将允许更准确和更早的诊断，为参与突变家族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，并提供重要的新见解FTLD病理学。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.