Mechanisms of Stimulating Innate Immunity

描述（由申请人提供）：抗菌素耐药性的传播迅速超过了新型抗生素的开发，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，宿主刺激很可能被证明是微生物适应性遗传过程的一个更困难的目标，因为它使宿主-病原体相互作用失衡，而不是简单地杀死病原体或阻止其复制。为了获得这笔赠款，我将利用一个新的C。elegans liqui感染检测，我已经开发和特点。C.线虫具有与人类相似的进化上保守的先天免疫途径。在具体目标1中，将描述在我早期的努力中确定的具有免疫刺激特性的小分子所使用的机制。我还将通过测试或激活和极化小鼠巨噬细胞来确定这种活性是否是保守的。以这种方式，将获得对脊椎动物模型生物体中免疫激活机制的深入了解，可能为人类治疗确定新的靶点。对于特定目标2，我将研究在特定细菌食物源上饲养蠕虫诱导的免疫刺激机制。发现的刺激机制可能会产生新的见解肠道感染，自身免疫性疾病和肠道炎症条件。每个目标的一部分将进行，而我完成我的指导博士后奖学金，但都将完成一旦我有一个独立的位置。 我目前的环境，无论是在机构和实验室的水平，是杰出的。弗雷德·奥苏贝尔博士是我的导师之一，他是C.线虫的先天免疫Ruvkun博士是C.优雅我有机会得到这两位模范科学家的共同指导，最大限度地提高了我的培训。此外，我被联合任命的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。 我感兴趣的是发展对非生物（例如，高温、缺氧、氧化应激）和生物应激（包括感染、炎症和癌症）。为此，我的职业生涯一直专注于收集探索这些途径所需的技能。我近期的职业计划包括发表正在进行的关于我开发的液体杀灭试验的宿主方面的分析。这将更坚实地奠定基础的调查结果，将在此期间获得补助金。在这一进程中的下一个重要步骤是过渡到一个独立的位置，并获得R 01赠款申请的初步数据，这将大大促进收购 这份赠款。

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.