Expanding insights into FTD disease mechanisms

额颞叶变性(FTLD)是早发性痴呆的常见原因，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发病的不同潜在机制是我的研究计划的一个基本兴趣领域。为了加速科学发现，我们采取了一种综合的方法，研究了由关键分子成员(例如TDP-43、PROGROGIN和tau)驱动的多种FTLD机制。我们还非常重视转化性研究，旨在确定急需的生物标记物和治疗方法，鉴于FTLD尚无治疗方法，这一领域尤为重要。我们努力揭示与TDP-43、tau和FTLD导致的突变相关的病理机制，并在高影响力的期刊上发表了开创性的发现。例如，在C9ORF72中发现G4C2重复扩增是FTLD最常见的已知原因后的五年，我的团队发现了该突变特有的一个新的神经病理特征，即由该扩增合成的重复二肽的蛋白质积累；在阐明与这些所谓的C9RAN蛋白相关的疾病机制方面取得了重大进展；确定了C9ORF72重复扩张携带者的有希望的治疗策略和潜在的生物标志物；并建立了第一个概括患者神经病理和临床特征的小鼠模型。我们的生产力受到梅奥诊所培养的卓越研究环境的影响，该诊所汇聚了高度互动和敬业的神经生物学家、遗传学家、神经病理学家和内科科学家，以及我们与世界知名专家在该领域建立的众多合作。在此，我们建议通过解决有影响力的问题来扩大我们的发现，其中一些问题可能风险很高，但所有这些问题都有明显的潜力对该领域产生变革。重要的是，R35机制的性质将允许我们灵活地探索从我们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。总之，为了增进我们对FTLD的理解和开发治疗方法，我们建议在三个主要领域进行机械性和转化性研究：1)C9ORF72-FTLD-TDP；2)GRN-FTLD-TDP；以及3)FTLD-Tau。我们将探索各种治疗方法，寻找脑脊液和血液中与疾病相关的生物标志物，并发展和改进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.