Investigating the Role of the Histone Demethylase LSD1/KDMI in Neurodegeneration

 描述（由申请人提供）：阿尔茨海默病（AD）和相关的额颞叶痴呆症（FTD）共同影响约540万美国人，每年导致近2000亿美元的医疗保健和长期患者护理费用。然而，尽管存在这一巨大的健康问题，但我们对这些疾病的理解仍存在很大差距。我们已经在小鼠中发现了一种新的表观遗传机制，该机制在维持分化的海马神经元中发挥作用，并且我们将这种机制与AD和FTD联系起来。我们假设这种表观遗传机制受到老年人病理性蛋白质聚集体的抑制，导致不适当的转录（包括干细胞转录的重新激活）和神经元细胞死亡。在这个提议中，我们将在我们的小鼠模型以及人类患者的样本中研究这种新的表观遗传途径。此外，由于（与其他痴呆模型不同）我们的小鼠模型表现出大量海马神经元细胞死亡，我们将联合收割机与其他小鼠模型结合，以确定神经元细胞死亡的共同机制，如神经变性中发生的那样。 这一建议的重要性在于，它在机制上弥合了AD和FTD病例中观察到的病理性聚集体与这些痴呆背后的神经元细胞死亡之间的差距。基于这些研究，有可能在AD和FTD患者中治疗靶向这一新途径。这些研究还将研究神经元细胞死亡的常见机制，这些机制可以作为其他潜在的治疗靶点。因此，该提案直接响应了国家应对阿尔茨海默病计划的优先事项;调查可以有针对性地进行治疗的新途径。此外，该提议具有创新性，因为它将维持分化细胞命运所需的新表观遗传机制与AD和FTD联系起来。因此，这些研究也将显著影响我们对基础发育生物学和干细胞生物学的理解。

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) and the related Frontotemporal Dementia (FTD) together affect ~5.4 million Americans and result in nearly $200 billion annually in healthcare and long-term patient care costs. Yet despite this massive health problem, large gaps remain in our understanding of these diseases. We have uncovered a novel epigenetic mechanism in mice that functions in the maintenance of differentiated hippocampus neurons, and we have linked this mechanism to AD and FTD. We hypothesize that this epigenetic mechanism is inhibited by pathological protein aggregates in aging adults, resulting in inappropriate transcription (including reactivation of stem cell transcription) and neuronal cell death. In this proposal, we will investigate this new epigenetic pathway in our mouse model as well as in human patient's samples. In addition, because (unlike other dementia models) our mouse model exhibits massive hippocampus neuronal cell death, we will combine our mouse model with other mouse models to identify common mechanisms of neuronal cell death, as occur in neurodegeneration. This proposal is significant in that it mechanistically bridges the gap between pathological aggregates observed in AD and FTD cases and the neuronal cell death that underlies these dementias. Based on these studies, it may be possible to therapeutically target this new pathway in AD and FTD patients. These studies will also investigate common mechanisms of neuronal cell death that could serve as additional potential therapeutic targets. As a result, this proposal is directly responsive to the National Plan to Address Alzheimer's Disease priority; to investigate new pathways that can be targeted for treatment. In addition, this proposal is innovative because it links a novel epigeneti mechanism that is required to maintain differentiated cell fates to AD and FTD. As a result, these studies will also significantly impact our understanding of basic developmental biology and stem cell biology.