Expanding insights into FTD disease mechanisms

额颞叶变性（FTLD）是早发性痴呆的常见病因，包括一组具有显著遗传、临床和神经病理异质性的疾病。了解FTLD发病机制的多样性是我的研究计划的一个基本领域。为了加速科学发现，我们采用了一种全面的方法，研究了由关键分子参与者（例如，TDP-43、颗粒蛋白前体和tau）。我们还非常重视转化研究，以确定急需的生物标志物和疗法，这是一个特别重要的领域，因为FTLD没有治疗方法。我们努力揭示与TDP-43，tau和FTLD相关的致病机制，已经在高影响力的期刊上发表了开创性的发现。例如，在发现C9 ORF 72中的G4 C2重复扩增作为FTLD的最常见已知原因的五年中，我的小组鉴定了特异于该突变的新的神经病理学标志，即由扩增合成的重复二肽的蛋白质的积累;在阐明与这些所谓的c9 RAN蛋白相关的疾病机制方面取得了重大进展;确定了C9 ORF 72重复扩增载体的有希望的治疗策略和潜在的生物标志物;并开发了第一个小鼠模型，以重现患者的神经病理学和临床特征。我们的生产力受到马约诊所良好的研究环境的影响，该诊所汇集了高度互动和专注的神经生物学家，遗传学家，神经病理学家和内科科学家，以及我们与该领域世界知名专家的众多合作。在此，我们建议通过解决有影响力的问题来扩展我们的发现，其中一些可能是高风险的，但所有这些都具有明显的变革潜力。重要的是，R35机制的性质将使我们能够灵活地探索从我们的发现和其他人的发现中出现的有趣的新方向，确保我们的研究保持及时和相关。总的来说，为了促进我们对FTLD的理解和开发治疗方法，我们提出了与三个主要领域相关的机制和翻译研究：1）C9 ORF 72连接的FTLD-TDP; 2）GRN连接的FTLD-TDP;和3）FTLD-Tau。我们将探索各种治疗方法，寻求确定脑脊液和血液中疾病相关的生物标志物，并开发和改进FTLD动物模型。

Frontotemporal lobar degeneration (FTLD), a common cause of early-onset dementia, encompasses a group of disorders with significant genetic, clinical and neuropathological heterogeneity. Understanding the diverse underlying mechanisms of FTLD pathogenesis is a fundamental area of interest of my research program. To accelerate scientific discovery, we have adopted a comprehensive approach that investigates multiple FTLD mechanisms driven by key molecular players (e.g., TDP-43, progranulin, and tau). We also place great emphasis on translational research geared towards identifying much needed biomarkers and therapies, an area of particular importance given that there exists no treatment for FTLD. Our endeavors to uncover the pathomechanisms associated with TDP-43, tau and FTLD-causing mutations have yielded seminal findings published in high-impact journals. For instance, in the five years since the discovery of the G4C2 repeat expansions in C9ORF72 as the most common known cause of FTLD, my group identified a new neuropathological hallmark specific to this mutation, namely the accumulation of proteins of repeating dipeptides synthesized from the expansion; made significant strides in elucidating mechanisms of disease relating to these so-called c9RAN proteins; identified promising therapeutic strategies and potential biomarkers for C9ORF72 repeat expansion carriers; and developed the first mouse model to recapitulate both neuropathological and clinical features of patients. Our productivity is influenced by the excellent research environment fostered at Mayo Clinic, which brings together highly interactive and devoted neurobiologists, geneticists, neuropathologists and physician scientists, as well as the numerous collaborations we have forged with world-renowned experts in the field. Herein, we propose to extend our discoveries by addressing impactful questions, some of which may be high risk, but all with clear potential to be transformative to the field. Of importance, the nature of the R35 mechanism will allow us the flexibility to explore intriguing new directions that emerge from our findings and those of others, ensuring that our studies remain timely and relevant. Overall, with the goal of advancing our understanding and developing therapies for FTLD, we propose mechanistic and translational investigations relating to three main areas: 1) C9ORF72-linked FTLD-TDP; 2) GRN-linked FTLD-TDP; and 3) FTLD-Tau. We will explore various therapeutic approaches, seek to identify disease-relevant biomarkers in cerebrospinal fluid and blood, and develop and improve FTLD animal models.