Mechanisms of Stimulating Innate Immunity

描述(申请人提供)：抗菌素耐药性的传播迅速超过了新型抗生素的发展，对人类健康和福祉造成了迫在眉睫的危险。避免这种健康危机的一种方法是确定刺激宿主先天免疫系统的机制，从而增加微生物的清除。此外，宿主刺激可能会被证明是微生物适应遗传过程的一个更困难的目标，因为它破坏了宿主与病原体的相互作用，而不是简单地杀死病原体或阻止其复制。对于这笔赠款，我将使用我开发和表征的一种新的秀丽线虫感染检测方法。线虫拥有与人类相似的进化保守的先天免疫途径。在具体目标1中，将描述我在早期工作中确定的具有免疫刺激特性的小分子所使用的机制。我还将通过检测小鼠巨噬细胞的激活和极化来确定这种活性是否保守。通过这种方式，将获得对脊椎动物模型生物免疫激活机制的洞察，潜在地确定人类治疗的新靶点。对于特定的目标2，我将研究一种通过饲养蠕虫对特定的细菌食物来源诱导免疫刺激的机制。已发现的刺激机制可能会对肠道感染、自身免疫性疾病和肠道炎症状况产生新的见解。每个目标的一部分将在我完成我的指导博士后奖学金期间完成，但这两个目标都将在我有独立的职位后完成。我目前的环境，无论是机构层面还是实验室层面，都是出色的。弗雷德·奥苏贝尔博士是我的导师之一，他开创了对线虫先天免疫的研究。Ruvkun博士是线虫应激反应领域的领导者。我有机会得到这两位模范科学家的共同指导，最大限度地发挥了我的培训效果。此外，马萨诸塞州总医院和哈佛医学院的设施、设备和科学环境都是世界上最好的，我是联合任命的。我感兴趣的是加深对非生物(如高温、低氧、氧化应激)和生物应激(包括感染、炎症和癌症)的综合反应的理解。为此，我的职业生涯一直专注于积累探索这些途径所需的技能。我近期的职业计划包括发表关于我开发的液体杀灭试验宿主方面的正在进行的分析。这将为在这笔赠款期间获得的调查结果奠定更坚实的基础。这一进程的下一个重要步骤包括过渡到独立的职位并为R01拨款申请获取初步数据，这将极大地促进收购 这笔赠款的。

DESCRIPTION (provided by applicant): The spread of antimicrobial resistance is quickly outstripping the development of novel antibiotics, creating a looming danger for human health and well-being. One means for avoiding this health crisis is the identification of mechanisms to stimulate the innate immune system of the host instead, enabling increased microbial clearance. In addition, host stimulation is likely to prove a more difficult target for the adaptive genetic processes of microbes, as it unbalances the host-pathogen interaction, rather than simply killing the pathogen or preventing its replication. For this grant, I will utilize a novel C. elegans liqui infection assay that I have developed and characterized. C. elegans possesses evolutionarily conserved innate immune pathways similar to those of humans. In Specific Aim 1, the mechanisms used by small molecules with immunostimulatory properties identified in my earlier efforts will be characterized. I will also determine whether this activity is conserved by testing or activation and polarization of murine macrophages. In this fashion, insights into mechanisms of immune activation in vertebrate model organisms will be gained, potentially identifying novel targets for human therapeutics. For Specific Aim 2, I will investigate a mechanism of immune stimulation induced by rearing worms on a specific bacterial food source. The stimulatory mechanisms uncovered may yield new insights into intestinal infections, autoimmune disorders, and intestinal inflammatory conditions. Portions of each aim will be undertaken while I complete my mentored postdoctoral fellowship, but both will be completed once I have an independent position. My current environment, at both the institutional and the laboratory levels, is outstanding. Dr. Fred Ausubel, one of my mentors, pioneered the study of C. elegans innate immunity. Dr. Ruvkun is a leader in the field of stress responses in C. elegans. I've had the opportunity to be co-mentored by both of these exemplary scientists, maximizing my training. In addition, the facilities, equipment, and scientific environment at Massachusetts General Hospital and Harvard Medical School, where I am jointly appointed, are amongst the best in the world. I am interested in developing increased understanding about the integrated the responses to abiotic (e.g., hyperthermia, hypoxia, oxidative stress) and biological stresses (including infection, inflammation, and cancer). Toward that end, my career has focused on assembling the skills necessary to probe these pathways. My immediate career plans include publication of ongoing analysis regarding the host aspect of the liquid killing assay that I have developed. This will more solidly ground the findings that will be acquired during this grant. The next important step in that progression involves a transition to an independent position and acquiring preliminary data for an R01 grant application, which will be greatly facilitated by the acquisition of this grant.