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1人将年满60岁。衰老的一个标志是 免疫学变化增加了这一人群对炎症性年龄相关疾病的易感性， 阻碍对感染和疫苗反应，降低再生能力。使用合成生物材料 在多种方式，包括药物输送，疫苗，假肢，和组织工程支架，以促进 组织再生免疫系统是任何损伤和植入物的第一反应者，它指导 对这些材料的异物反应（FBR）-对于合成材料，它通常是促炎性的，并导致 疤痕这种免疫反应不仅取决于材料本身，还取决于组织位置和 植入部位的基础病理生理学（患者的人口统计学背景和健康状况）。因此 “生物相容性”的概念取决于宿主免疫系统的当前状态 受宿主年龄和性别的影响随着人口老龄化，迫切需要了解 年龄特异性促炎性偏斜免疫系统改变对合成材料的免疫应答 植入物.这项工作的目标是确定免疫系统中的关键生物因子和靶点。 这些与免疫调节合成材料一起用于老年人口的组织再生。的 最重要的假设是，老年免疫失调对效应状态化合物， 对合成材料有不良反应。使用先前描述的促纤维化支架治疗慢性非纤维化性血管病变。 愈合创伤小鼠模型，结合测序技术和表型分析， 在K99阶段，将阐明老化FBR（目标1）中的细胞-细胞通信网络以及 先天性和适应性免疫在整个生命周期内对合成材料的反应发生变化（目标2）。期间 独立研究阶段（R 00），我们将设计多阶段合成材料系统，以控制 组织工程中的老年免疫反应失调。开发新型免疫调节生物材料是 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，使候选人做好准备， 成为顶级研究机构的主要研究员，研究免疫控制的界面， 伤口愈合和老化的合成生物材料为基础的治疗。

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.