Project 4: Consequences of Retrotransposable Element Activation in the Central Nervous System

项目摘要： 阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，其重要性日益增加 全球人口老龄化。尽管经过几十年的研究，目前还没有有效的治疗AD的方法， 并且散发性AD的分子原因仍然难以捉摸。AD病理学与 衰老的大脑;了解脑细胞类型中与年龄相关的功能障碍的来源是开发 治疗干预。越来越多的逆转录转座因子（RTE），包括活跃的人类RTE， LINE 1（L1）与衰老功能障碍密切相关，与AD中观察到的变化非常相似，包括 增加无菌性炎症、表观遗传不稳定性和最终的神经毒性。这是一个诱人的 有机会追求L1作为一个可药用的目标，以阻止失控的神经炎症和神经变性， AD.为此，该提案利用了最先进的人类体外建模系统，包括 衰老诱导神经元（iN）、诱导多能干细胞（iPSC）衍生的星形胶质细胞和胶质细胞富集的胶质细胞（Glial enriched 类器官研究L1激活在疾病相关疾病中的衰老和细胞类型依赖性后果 细胞类型。 使用一组AD患者和年龄匹配的健康对照衍生神经元，Gage团队将 测试L1活性对两种散发性AD病理学的贡献：神经元衰老和整体松弛 染色质。接下来，研究小组将直接测试L1激活对于自发性脑损伤的新发现的必要性。 老年AD神经元培养物中的神经炎症。最后，为了避免狭窄的以神经元为中心的AD模型， 将我们的分析扩展到包括患者来源的星形胶质细胞和富含胶质细胞的脑类器官，以了解 L1在大脑的其他细胞类型和3D组织特异性环境中诱导炎症的后果。 这项建议提供了与其他参与项目密切合作的充分机会 成员患者细胞系和衍生的神经细胞可以很容易地提供给合作者进行靶向分析 一组经过临床验证的人体样本测序和遗传分析与 在AD的小鼠和苍蝇模型中协作策略，为验证结果提供平台， 未来的机械研究Gage团队的策略包括通过合作设计L1靶向载体 核心，以确保跨模型系统的可靠干预和读数。这个项目，在努力配合， 的合作者，将提供最彻底的检查后果的L1激活的AD大脑 迄今为止，潜在的开拓性新的治疗策略，这种疾病的巨大关注。

Project Summary: Alzheimer’s disease (AD) is a devastating neurodegenerative condition that is of increasing importance to an aging global population. Despite decades of research, there are currently no effective treatments for AD, and the molecular causes for sporadic forms of AD remain elusive. AD pathologies are intimately tied to the aging brain; and understanding sources of age-related dysfunction in brain cell types are key for developing therapeutic interventions. Increasingly, retrotransposable elements (RTEs), including the active human RTE LINE1 (L1), are conspicuously linked to aging dysfunctions that closely resemble changes seen in AD, including increased sterile inflammation, epigenetic instability and ultimately neurotoxicity. This presents the enticing opportunity of pursuing L1 as a druggable target to halt runaway neuroinflammation and neurodegeneration in AD. To this end, this proposal utilizes a trifecta of state-of-the-art human in vitro modeling systems, including aged induced neurons (iNs), induced pluripotent stem cell (iPSC) derived astrocytes, and glial enriched organoids to investigate the aging- and cell type-dependent consequences of L1 activation in disease relevant cell types. Using a cohort of AD patients and healthy age-matched controls derived neurons, the Gage team will test the contribution of L1 activity to two sporadic AD pathologies: neuronal senescence, and global relaxation of chromatin. Next, the team will directly test the necessity of L1 activation for the novel finding of spontaneous neuroinflammation in aged AD neuronal cultures. Finally, to avoid a narrow neuron-centric model of AD, we will extend our analyses to include patient-derived astrocytes and glial-enriched brain organoids to understand the consequences of L1 induced inflammation in other cell types of the brain and in 3D tissue specific contexts. This proposal provides ample opportunity for close collaborations with other participating project members. Patient cell lines and derived neural cells can be readily provided to collaborators for targeted analyses on a consistent set of clinically verified human samples. Sequencing and genetic analyses are paired with collaborating strategies in both mouse and fly models of AD, providing a platform for verification of results and future mechanistic research. The Gage team’s strategy involves L1 targeting vectors designed by collaborating cores to ensure reliable interventions and readouts across model systems. This project, in tandem with the efforts of collaborators, will provide the most thorough examination of consequences of L1 activation on the AD brain to date, potentially pioneering new therapeutic strategies for this disease of immense concern.