Non-canonical cGAS signaling in DNA damage response

DNA 损伤反应中的非典型 cGAS 信号传导

• 批准号: 10287373
• 负责人: Nagaraj Kerur
• 金额: $ 34.27万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-05 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10287373
• 关键词: Accounting; Address; Administrative Supplement; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Model; Antiviral Agents; Apoptotic; Appearance; Autopsy; Award; Biochemical; Brain; Cell Culture Techniques; Cells; Cyclic GMP; DNA; DNA Damage; DNA Double Strand Break; Data; Dementia; Development; Disease; Funding; Future; Goals; Grant; Immunologist; Inflammation; Interferons; Laboratories; Link; Microglia; Molecular; Molecular Profiling; Nerve Degeneration; Neurologic Symptoms; Parents; Pathogenesis; Pathologic; Pathway interactions; Process; Reporting; Role; Signal Transduction; Stimulator of Interferon Genes; Therapeutic; Tissue Donors; United States National Institutes of Health; brain tissue; insight; mouse model; novel; pre-clinical; response; sensor; therapeutic target

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.

阿尔茨海默病中DNA损伤诱导的cGAS信号转导 本申请按照NOT-AG-20-034提交。本行政管理报告中提议的研究 对我们资助的NIH资助1 R 01 AI 148741（DNA损伤中的非经典cGAS信号传导）的补充申请 反应）将提供新的功能性见解，以了解DNA损伤驱动的cGAS信号传导活性 有助于AD的发病机制。 阿尔茨海默病（Alzheimer's disease，AD）是最常见的痴呆症，约占所有痴呆症的60-70% 国际吧DNA损伤的持续积累是衰老的标志之一，与AD有关， 多种神经退行性疾病DNA双链断裂（DSB）的增加在治疗后 多项研究已经报道了AD患者的死亡脑组织。此外，多个临床前小鼠 模型显示，在小鼠中观察到增加的DNA损伤和相关的分子特征， 大脑，这些证据的出现先于神经症状的发作，或 在这些动物模型中的神经变性。有趣的是，在动物模型中减少DNA损伤的方法已经被证明是可行的。 显示改善AD的病理特征。更好地理解DNA调控机制 在AD的背景下，脑中的损伤信号传导具有鉴定该疾病的治疗靶点的潜力。 先天性DNA传感器，环GMP-AMP合酶（cGAS），最近已经成为一个关键的反应， DNA损伤，其中由受损DNA引发的cGAS活化触发炎症和凋亡 通过DDR诱导途径。在本补充请求中，我们建议提供新的功能见解， DNA损伤诱导的cGAS信号传导活性是否有助于AD的发病机制。这一目标将是 通过以下具体目标来解决： 1.确定cGAS信号传导脑组织成分的丰度、激活状态和分布 来自AD患者和AD的临床前小鼠模型的供体。 2.确定cGAMP-STING信号传导参与小胶质细胞培养物中暴露的Aβ。 总的来说，这些研究将介绍cGAS信号传导在AD中的作用，并为以下方面提供分子基础： 在临床前小鼠模型中靶向cGAS-STING驱动的干扰素和DNA损伤反应信号传导。作为 因此，这一补充请求是在积极的父母NIH奖的范围内，并有可能 刺激新研究，以检查cGAS-STING途径的新分子和生化机制， AD.我们预测，在AD中建立这一新途径将刺激AD的部分额外活动， 神经科学家，免疫学家和细胞生物学家，从而导致破译和潜在的进展， 治疗AD和相关痴呆症。这一补充也将使我们的实验室能够通过以下方式发展对AD的关注： 生成额外的实验数据，这些数据可以用来提交直接针对AD的新提案。