Age and sex differences in the immune response to synthetic materials

项目摘要 世界卫生组织估计，到2030年，每6个人中就有一个人的年龄在60岁或以上。衰老的一个标志是 免疫变化增加了这一人群对炎症性年龄相关疾病的易感性， 阻碍对感染和疫苗的反应，并降低再生能力。使用合成生物材料 通过多种方式，包括药物输送、疫苗、假体和组织工程学中的支架，促进 组织再生。免疫系统是对任何损伤和植入的第一反应，它指导 对这些材料的异物反应(FBR)-对于合成材料，它通常是促炎的，并导致 伤痕累累。这种免疫反应不仅取决于材料本身，还取决于组织的位置和 植入部位的潜在病理生理学(患者的人口统计背景和健康状况)。因此， 生物相容性的概念依赖于宿主免疫系统的当前状态，这在很大程度上 受主持人年龄和性别的影响。随着人口老龄化，迫切需要了解 年龄特异性促炎倾斜免疫系统改变对合成材料的免疫反应 植入物。这项拟议工作的目标是确定免疫系统中的关键生物因素和靶点。 这些具有免疫调节作用的合成材料用于老龄化人口的组织再生。这个 最重要的假设是，老年人对效应器状态的免疫失调使 对合成材料的不良反应。使用先前描述的促纤维化支架在慢性非 小鼠创伤愈合模型，结合测序技术和表型分析，进行实验 在K99阶段将阐明老年FBR中的小区间通信网络(目标1)以及 先天免疫和获得性免疫对合成材料的反应随性别而变化(目标2)。在.期间 独立研究阶段(R00)，我们将设计多阶段合成材料系统来控制 组织工程中的老年免疫反应失调。正在开发新的免疫调节生物材料 对于解决FBR以减少不必要的植入物相关并发症至关重要。完成这项研究 将提供培训机会以掌握新的技术方法，使应聘者做好准备 成为一家顶级研究机构的主要研究员，研究疫苗免疫控制的界面 从伤口愈合和老化到基于合成生物材料的疗法。

Project Summary The WHO estimates that 1 in 6 people will be 60 years or older by 2030. A hallmark of aging is the immunological changes that increase susceptibility of this population to inflammatory age-related diseases, hinder response to infections and vaccines, and lower regenerative capacity. Synthetic biomaterials are used in multiple ways including drug delivery, vaccines, prosthetics, and scaffolds in tissue engineering to promote tissue regeneration. The immune system is the first responder to any injury and implants, and it directs the foreign body reaction (FBR) to these materials—for synthetic materials it is often proinflammatory and leads to scarring. This immune response is not only dependent on the material itself but both the tissue location and underlying pathophysiology (patient’s demographic background and health) of the implant site. Thus, the concept of “biocompatibility” is dependent on the current state of the host immune system which is significantly influenced by the host’s age and sex. With an aging population there is a critical need to understand how the age-specific proinflammatory skewed immune system alters the immune response to synthetic material implants. The goal of this proposed work is to identify key biologic factors in the immune system and target these with immunomodulatory synthetic materials for use in the aging population for tissue regeneration. The overarching hypothesis is that the aged immune dysregulation towards an effector state compounds the adverse reaction to synthetic materials. Using a previously described pro-fibrotic scaffold in a chronic non- healing wound mouse model, combined with sequencing techniques, and phenotypic analysis, the experiments in the K99 phase will elucidate the cell-cell communication networks in the aged FBR (Aim 1) as well as the innate and adaptive immune shifts in response to synthetic materials over lifespan by sex (Aim 2). During the independent research phase (R00), we will engineer multi-stage synthetic material systems to control the dysregulated aged immune response in tissue engineering. Developing new immunomodulatory biomaterials is critical to addressing the FBR to reduce unwanted implant related complications. Completion of this research will provide training opportunities to master new technical approaches that will prepare the candidate to become a primary investigator at a top-tier research institution studying the interface of the immune control of wound healing and aging to synthetic biomaterial-based therapies.