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

 描述(申请人提供)：阿尔茨海默病(AD)和相关的额颞叶痴呆(FTD)每年影响约540万美国人，导致近2000亿美元的医疗保健和长期患者护理成本。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然存在很大差距。我们在小鼠身上发现了一种新的表观遗传学机制，它在维持分化的海马神经元方面发挥作用，我们将这一机制与AD和FTD联系起来。我们假设，这种表观遗传机制被老年人中的病理性蛋白质聚集体抑制，导致不适当的转录(包括干细胞转录的重新激活)和神经细胞死亡。在这个提案中，我们将在我们的小鼠模型中以及在人类患者的样本中研究这一新的表观遗传途径。此外，由于我们的小鼠模型(与其他痴呆模型不同)表现出大量的海马神经细胞死亡，我们将结合我们的小鼠模型和其他小鼠模型来识别神经细胞死亡的常见机制，如神经退行性变中所发生的。这一建议意义重大，因为它机械地弥合了AD和FTD病例中观察到的病理聚集和这些痴呆背后的神经细胞死亡之间的差距。基于这些研究，有可能在治疗上针对AD和FTD患者的这一新途径。这些研究还将调查神经细胞死亡的常见机制，这些机制可能成为额外的潜在治疗靶点。因此，这项提议直接响应了解决阿尔茨海默病优先问题的国家计划；调查可作为治疗目标的新途径。此外，这一建议是创新的，因为它将维持分化细胞命运所需的一种新的表观机制与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.