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

项目摘要 免疫系统功能障碍是许多神经退行性疾病的共同标志;然而， 对于炎症是否抑制或加重疾病病理仍存在争议。最近有 证明了通过消除cGas/STING来减轻小鼠中的干扰素（IFN）信号传导， 通路，在PARK-/-和PINK 1-/-背景中预防帕金森病的神经变性模型， 携带易错线粒体DNA聚合酶（PolG-突变体）的小鼠。目前尚不清楚， 由STING（干扰素基因刺激因子）调节的免疫信号传导导致了 多巴胺能神经元这种PD诱导的神经元死亡可以在遗传上可追踪的和快速的 复制模式生物黑腹果蝇（Drosophila melanogaster），其具有良好表征的先天免疫应答。 我假设从果蝇到人类的先天免疫反应途径是保守的，如NF-kB和 JAK/STAT通路响应于线粒体质量的遗传和病理抑制而被激活 控制路径。在我的研究训练计划中，我建议测试线粒体DNA的综合作用， 突变积累与感染触发的免疫信号传导对多巴胺能神经元变性的影响 帕金森病的多种遗传模型。此外，我打算测试神经元细胞死亡的抑制因子， 这种受损的线粒体自噬和感染的双重打击模型，以鉴定潜在的新的神经元介导剂， 死亡拟议的研究还旨在表征细胞溶质核苷酸传感的发散机制 在果蝇中，缺乏典型的上游激活剂cGas。循环源的识别 激活Sting的核苷酸将极大地增强我们对先天免疫进化历史的理解， 途径，并可能导致发现新的组件在传感胞质DNA，无论是从外来的 来源，如病毒或细菌和内源性DNA从受损的线粒体或细胞核释放。这 奖学金培训计划提供了新的智力挑战，科学技能培训的机会， 专业成长，以及职业发展和求职的具体设计。拟议研究 和培训计划将为申请人提供必要的技能，以成功地在具有挑战性的学术 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.