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

1351688 Jewell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，以及更好地了解对植入生物材料的免疫反应的调节。 免疫应答由淋巴结（LN）中协调的相互连接的信号传导途径介导。因此，所有疫苗必须到达淋巴结才有效。 生物材料，如合成聚合物，正在被广泛研究作为疫苗载体，因为它们提供了受控释放和货物的共同交付。最近，几种生物材料与激活炎症免疫途径的内在特性相关，即使在没有其他免疫信号的情况下。然而，直接信息的影响，生物材料在淋巴结或机制，这些影响调节免疫力是很大程度上缺乏。由于生物材料疫苗在外周位置（例如，总的假设是生物材料的物理化学性质和结合的免疫信号的组合和递送动力学两者限定了对LN微环境和所产生的全身免疫应答的影响。 为了解决这个问题，PI将开发一个新的平台，直接将生物材料输送到LN，以控制LN中生物材料和疫苗组分的浓度和输送动力学。 具体目的是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活化和全身反应的影响，2）研究从生物材料颗粒释放的抗原和佐剂在活化LN中的作用，3）剖析LN中和LN之间抗原/佐剂呈递密度的影响，和4）将生物材料载体激活的信号传导途径与临床批准的疫苗佐剂相关的特征进行比较。拟议的研究将解决聚合物如何影响LN激活以塑造免疫力，其在疫苗开发以及理解和调节对生物材料的免疫应答方面具有重要的分支。 更具体地说，所提出的研究将提供1）生物材料如何在免疫信号存在和不存在的情况下影响局部LN结构的基本信息，2）LN的局部变化如何调节全身免疫的知识，3）生物材料的控释和固有聚合物免疫活性在诱导反应中发挥的相对作用，和4）两类关键生物材料与批准的佐剂相比的信号传导谱。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具有挑战性的疾病仍然绕不开疫苗的功效。 拟议的研究将对疫苗领域产生重大影响，更一般地说，将对理解在存在和不存在免疫信号的情况下对生物材料的免疫反应产生重大影响。 特别是，拟议的研究可能有助于克服目前疫苗开发的技术限制，同时产生关于生物材料和LN之间相互作用的基础知识。 拟议的研究与教育计划相结合，以促进研究曝光和职业机会的认识，包括生物材料，免疫学和疫苗。这将通过与高需求的学校合作，支持社区外展计划以及本科生，研究生和博士后研究人员的培训来实现。 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率，并将为本科生，研究生和博士后研究人员提供研究教育的培训机会。

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.