Understanding the role of innate immunity and Sting-mediated inflammation in models of Parkinsons's Disease in Drosophila melanogaster

项目摘要 免疫系统故障是许多神经退行性疾病的共同标志；然而， 炎症是否抑制或加剧了疾病的病理仍存在争议。那是最近的事 证明了通过消除cGAS/STIN来缓解小鼠的干扰素信号 途径，在Park-/-和PINK1-/-背景下预防帕金森病的神经退行性变模型， 小鼠携带容易出错的线粒体DNA聚合酶(Polg-Mutator)。目前还不清楚 受干扰素基因刺激物(STIN)调控的免疫信号是导致细胞免疫功能丧失的原因之一 多巴胺能神经元。这种PD诱导的神经元死亡可以在基因上可追踪和快速地模拟 繁殖模式生物黑腹果蝇，具有良好的先天免疫反应。 我推测，从苍蝇到人类的先天免疫反应通路，如核因子-kB和 JAK/STAT通路被激活，以响应线粒体质量的遗传和病理抑制 控制路径。在我的研究训练计划中，我建议测试线粒体DNA的组合效应 感染触发的免疫信号对小鼠多巴胺能神经元变性的突变积累 帕金森氏病的多种遗传模型。此外，我打算测试神经细胞死亡的抑制因子 这种丝裂原吞噬和感染受损的双重打击模型可以识别潜在的神经元新介质 死亡。这项拟议的研究还旨在描述胞质核苷酸感测的不同机制。 通过在缺乏典型上游激活剂cGAS的果蝇中刺痛。旋回波源的识别 激活Sting的核苷酸将极大地增强我们对先天免疫进化史的理解 途径，并可能导致发现检测胞浆DNA的新成分，这两种成分都来自国外 病毒或细菌等来源，以及从受损的线粒体或细胞核中释放的内源性DNA。这 奖学金培训计划提供了新的智力挑战、科学技能培训和 职业成长，以及职业发展和求职的具体设计。拟议的研究 培训计划将为申请者提供必要的技能，以在具有挑战性的学术工作中取得成功 研究环境。

Project Summary Immune system malfunction is a common hallmark in many neurodegenerative diseases; however, controversy remains whether inflammation suppresses or exacerbates disease pathology. It was recently demonstrated that alleviation of interferon (IFN) signaling in mice, through elimination of the cGas/STING pathway, prevented neurodegeneration models of Parkinson’s Disease in PARK-/- and PINK1-/- backgrounds, with mice harboring an error-prone mitochondria DNA polymerase (PolG-mutator). It remains unknown how the immunity signaling regulated by STING (Stimulator of Interferon Genes) is contributing to loss of the dopaminergic neurons. This PD-induced neuronal death can be modeled in the genetically traceable and rapidly reproducing model organism Drosophila melanogaster, which has a well-characterized innate immune response. I hypothesize that innate immune response pathways conserved from flies to humans, such as the NF-kB and JAK/STAT pathways are activated in response to genetic and pathological inhibition of mitochondria quality control pathways. In my research training plan, I propose to test the combined effects of mitochondria DNA mutation accumulation with infection-triggered immune signaling on dopaminergic neuron degeneration in multiple genetic models of Parkinson’s Disease. Further, I intend to test suppressors of neuronal cell death in this double hit model of impaired mitophagy and infection to identify potentially novel mediators of neuronal death. The proposed research also aims to characterize the divergent mechanism of cytosolic nucleotide sensing by Sting in the fruit fly, which lack the canonical upstream activator cGas. Identification of the source of the cyclic nucleotides which activate Sting will greatly enhance our understand of the evolutionary history of innate immune pathways and could lead to the discovery of novel components in the sensing of cytosolic DNA, both from foreign sources such as viruses or bacteria and endogenous DNA released from damaged mitochondria or nuclei. This fellowship training plan provides novel intellectual challenges, opportunities for scientific skill training and professional growth, and concrete designs for career development and job searching. The proposed research and training plan will provide the applicant with the necessary skillsets to succeed in the challenging academic research environment.