Non-canonical cGAS signaling in DNA damage response

阿尔茨海默病中DNA损伤诱导的cGAS信号转导 本申请是根据NOT-AG-20-034提交的。本行政当局建议进行的研究 对我们资助的NIH拨款1R01AI148741(DNA损伤中的非规范cGAS信号)的补充请求 将为DNA损伤驱动的cGAS信号活动提供新的功能洞察 参与了AD的发病机制。 阿尔茨海默病(AD)是最常见的痴呆症，约占所有痴呆症的60%-70% 全世界。DNA损伤的持续积累是衰老的标志之一，已被认为与AD和 多种神经退行性疾病。损伤后DNA双链断裂(DSB)的积累 已有多项研究报道了致死性AD患者的脑组织。此外，多只临床前小鼠 模型显示，DNA损伤增加和相关的分子特征在 这些证据出现在出现神经症状或 这些动物模型中的神经退行性变。有趣的是，减少动物模型中的DNA损伤 能明显改善AD的病理特征。更好地理解DNA的调控机制 脑中的损伤信号，在AD的背景下，具有确定疾病治疗靶点的潜力。 与生俱来的DNA传感器，环状GMP-AMP合成酶(CGAS)，最近成为一种关键的反应因子 DNA损伤，由受损的DNA引发的cGAS激活引发炎症和细胞凋亡 通过DDR诱导的通路。在本补充请求中，我们建议提供新的功能洞察力 DNA损伤诱导的cGAS信号活性是否参与AD的发病。这一目标将是 通过以下具体目标加以解决： 1.测定cGAS信号通路脑组织成分的丰度、激活状态和分布 来自供者AD患者和AD临床前小鼠模型。 2.确定小胶质细胞培养中cGAMP-STING信号在A-β暴露中的作用。 总之，这些研究将介绍cGAS信号在AD中的作用，并提供一个分子基础 在临床前小鼠模型中靶向cGAS刺痛驱动的干扰素和DNA损伤反应信号。AS 这样，这项补充请求属于有效的父母NIH奖的范围，并有可能 激发新的研究以探索cGAS-STING途径的新的分子和生化机制 广告。我们预测，在阿尔茨海默病中建立这一新的途径将刺激部分 神经学家、免疫学家和细胞生物学家从而导致了破译方面的进展，并可能 治疗阿尔茨海默病及相关痴呆。这一补充还将使我们的实验室能够通过以下方式重点研究AD 生成额外的实验数据，可用于提交直接侧重于AD的新提案。

DNA damage-induced cGAS signaling in Alzheimer's disease This application is being submitted in accordance with NOT-AG-20-034. Studies proposed in this administrative supplement request to our funded NIH grant 1R01AI148741 (Non-canonical cGAS signaling in DNA damage response) will provide novel functional insights into whether DNA damage-driven cGAS signaling activity contributes to pathogenesis of AD. Alzheimer's disease (AD) is the most common form of dementia, accounting for about 60-70% of all the dementia worldwide. Persistent accumulation of DNA damage, one of the hallmarks of aging, has been linked to AD and numerous neurodegenerative conditions. Accumulation of elevated DNA double-strand breaks (DSBs) in post- mortem AD patient brain tissue has been reported by multiple studies. Additionally, multiple pre-clinical mouse models have revealed that increased DNA damage and associated molecular signatures are observed in the brain, and that appearance of these evidence precedes the onset of neurological symptoms or neurodegeneration in these animal model. Interestingly reducing DNA damage in animal models has been shown to ameliorate pathological features of AD. A better understanding of the mechanisms regulating DNA damage signaling in brain, in the context of AD holds potential for identifying therapeutic targets for the disease. The innate DNA sensor, cyclic GMP–AMP synthase (cGAS), has recently emerged as a critical responder to DNA damage wherein cGAS activation initiated by the damaged DNA triggers inflammation and apoptotic pathways via DDR induction. In this supplement request, we propose to provide new functional insights into whether DNA damage-induced cGAS signaling activity contribute to pathogenesis of AD. This objective will be addressed via following Specific Aims: 1. Determine the abundance, activation status and distribution of constituents of cGAS signaling brain tissue from donor AD patients and preclinical mouse models of AD. 2. Determine the involvement of cGAMP-STING signaling in Aβ-exposed in microglia cell cultures. Overall, these studies will introduce the role of cGAS signaling in AD and provide a molecular rationale for targeting cGAS-STING-driven interferon and DNA damage response signaling in preclinical mouse models. As such, this supplement request is within the scope of the active parent NIH award and has the potential to stimulate new studies for examining novel molecular and biochemical mechanisms of cGAS-STING pathway in AD. We predict that establishing this new pathway in AD will stimulate additional activity on the part of neuroscientists, immunologists and cell biologists thereby leading to progress in deciphering and potentially treating AD and related dementias. This supplement will also enable our laboratory to develop a focus on AD by generating additional experimental data that can be leveraged to submit new proposals focused directly on AD.