CAREER: Dissecting the role of biomaterials in lymph nodes to study and shape immunity

1351688珠宝本提案中描述的研究将生物工程与免疫学相结合，以产生关于生物材料如何与免疫细胞和组织相互作用的新知识。这一见解将有助于开发新的疫苗，并有助于更好地理解对植入的生物材料的免疫反应的调节。免疫反应是由相互连接的信号通路在淋巴结(LNS)中协调调节的。因此，所有疫苗都必须到达LNS才能有效。生物材料，如合成聚合物，作为疫苗载体正在被广泛研究，因为它们提供了可控释放和联合运送货物。最近，一些生物材料与激活炎症免疫途径的内在特性有关，即使在没有其他免疫信号的情况下也是如此。然而，关于生物材料在LNS中的影响或这些效应调节免疫的机制的直接信息在很大程度上是缺乏的。由于生物材料疫苗在周围位置(如肌肉)注射后到达LNS的效率低下(剂量的1%)，这种认识差距仍然存在。总体假设是，生物材料的物理化学性质和结合的免疫信号的结合和传递动力学定义了对LN微环境和由此产生的全身免疫反应的影响。为了解决这个问题，PI将利用一个新的平台，直接向LNS运送生物材料，以控制LNS中生物材料和疫苗组件的浓度和输送动力学。其具体目标是：1)在没有其他免疫信号的情况下，量化具有不同稳定性的生物材料对LN激活和全身反应的影响；2)研究从生物材料颗粒中释放的抗原和佐剂在激活LN中的作用；3)剖析抗原/佐剂呈递密度在LN内和跨LN呈现密度的影响；4)比较生物材料载体激活的信号通路和临床批准的疫苗佐剂相关的信号通路。更具体地说，拟议的研究将提供1)生物材料在没有和存在免疫信号的情况下如何影响局部LN结构的基本信息，2)局部LN变化如何调节系统免疫的知识，3)生物材料的控制释放和固有的聚合物免疫活性在诱导反应中所起的相对作用，以及4)两类关键生物材料与批准的佐剂相比的信号特征。更广泛的影响：疫苗对全球健康产生了非凡的影响，但艾滋病毒和癌症等挑战性疾病仍然避开了疫苗的效力。拟议的研究将对疫苗领域产生重大影响，更广泛地说，将有助于理解在没有免疫信号和存在免疫信号的情况下对生物材料的免疫反应。特别是，拟议的研究可能有助于克服疫苗开发中目前的技术限制，同时产生关于生物材料和LN之间相互作用的基础知识。拟议的研究与一项教育计划相结合，以促进研究接触和对结合生物材料、免疫学和疫苗的职业机会的认识。这将通过与高需求学校合作，支持社区推广计划，以及培训本科生、研究生和博士后研究人员来实现。这些教育和推广活动将有助于增加STEM学位和研究项目的高中生入学人数，并将为本科生、研究生和博士后研究人员提供研究教育培训机会。

1351688JewellThe studies described in this proposal integrate bioengineering with immunology to generate new knowledge on how biomaterials interact with immune cells and tissues. This insight will contribute towards the development of new vaccines as well as towards better understanding the modulating the immune responses towards implanted biomaterials. Immune responses are mediated by inter-connected signaling pathways coordinated in lymph nodes (LNs). Thus, all vaccines must reach LNs to be effective. Biomaterials, such as synthetic polymers, are being intensely studied as vaccine carriers because they offer controlled release and co-delivery of cargo. Several biomaterials have recently been associated with intrinsic properties that activate inflammatory immune pathways, even in the absence of other immune signals. However, direct information on the impact of biomaterials in LNs or the mechanisms by which these effects modulate immunity is largely lacking. This knowledge gap persists due to the inefficiency ( 1% of dose) with which biomaterial vaccines reach LNs after injection at peripheral locations (e.g., muscle).The overall hypothesis is that both the physicochemical properties of biomaterials and the combinations and delivery kinetics of incorporated immune signals define the impact on the LN microenvironment and the resulting systemic immune response. To address it, the PI will exploit a new platform that directly delivers biomaterials to LNs to control the concentration and delivery kinetics of biomaterials and vaccine components in LNs. The specific aims are to 1) quantify the impact of biomaterials with different stabilities on LN activation and systemic response in the absence of other immune signals, 2) study the role of antigen and adjuvant released from biomaterial particles in activating LNs, 3) dissect the influence of the density of antigen/adjuvant presentation in and across LNs, and 4) compare signaling pathways activated by biomaterial carriers to profiles associated with clinically approved vaccine adjuvants.Intellectual merit: The proposed studies will address how polymers impact LN activation to shape immunity, which has significant ramifications in vaccine development and in understanding and modulating the immune response towards biomaterials. More specifically, the proposed studies will provide 1) fundamental information of how biomaterials impact local LN structure in the absence and presence of immune signals, 2) knowledge of how local changes in LNs modulate systemic immunity, 3) the relative roles that controlled release and inherent polymer immune activity of biomaterials play in inducing responses, and 4) signaling profiles of two classes of key biomaterials compared with approved adjuvants.Broader impacts: Vaccines have had an extraordinary impact on global health, but challenging diseases such as HIV and cancer still circumvent vaccine efficacy. The proposed studies will have a significant impact on the vaccine field and, more generally, on understanding the immune response towards biomaterials in the absence and presence of immune signals. In particular, the proposed studies may help overcome current technical limitations in vaccine development, while generating fundamental knowledge on the interactions between biomaterials and LNs. The proposed studies are integrated with an education plan to promote research exposure and awareness of career opportunities incorporating biomaterials, immunology, and vaccines. This will be accomplished through partnering with high-need schools, supporting community outreach programs, and training of undergraduate, graduate, and postdoctoral researchers. These education and outreach activities will help increase enrolment of high school students in STEM degree and research programs and will provide training opportunities in research education for undergraduate, graduate, and postdoctoral researchers.