Age and sex differences in the immune response to synthetic materials

对合成材料的免疫反应存在年龄和性别差异

• 批准号: 10644064
• 负责人: Joscelyn Claraluz Mejias
• 金额: $ 10.09万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644064
• 关键词: Adaptive Immune System; Address; Adverse reactions; Age; Aging; Automobile Driving; Award; Biocompatible Materials; Biological; Biological Factors; Biomedical Engineering; Cell Communication; Cells; Chronic; Cicatrix; Communication; Compensation; Development; Devices; Disease; Drug Delivery Systems; Engineering; Female; Fibrosis; Flow Cytometry; Foreign-Body Reaction; Functional disorder; Goals; Health; Histology; Human; Hydrogels; Immune; Immune Targeting; Immune response; Immune system; Immunofluorescence Immunologic; Immunologics; Implant; Infection; Inflammation; Inflammatory; Injury; Innate Immune System; Institution; Location; Longevity; Macrophage; Maintenance; Modeling; Mus; Natural regeneration; Outcome; Patients; Persons; Phase; Phenotype; Population; Positioning Attribute; Predisposition; Prosthesis; Regenerative capacity; Regenerative engineering; Reporting; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Sex Differences; Site; Splenocyte; Stromal Cells; System; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissue Engineering; Tissues; Vaccines; Work; age difference; age related; aged; aging population; bioinformatics tool; biomaterial compatibility; career; cell type; design; experimental study; first responder; healing; immune function; immunoengineering; immunoregulation; implant design; implant material; improved; inflammatory marker; male; mouse model; neutrophil; non-healing wounds; particle; polycaprolactone; prevent; regenerative; response; response to injury; scaffold; senescence; sex; single-cell RNA sequencing; therapeutic target; tissue regeneration; tissue repair; training opportunity; tumor-immune system interactions; wound healing

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.

项目概要 世界卫生组织估计，到 2030 年，六分之一的人将达到 60 岁或以上。老龄化的一个标志是 免疫学变化增加了该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，并且使用合成生物材料较低的再生能力。 以多种方式，包括药物输送、疫苗、假肢和组织工程中的支架来促进 免疫系统是对任何损伤和植入物的第一反应者，它指导着组织再生。 对这些材料的异物反应 (FBR)——对于合成材料来说，它通常会促炎并导致 这种免疫反应不仅取决于材料本身，还取决于组织位置和疤痕。 植入部位的潜在病理生理学（患者的人口背景和健康状况）。 “生物相容性”的概念取决于宿主免疫系统的当前状态，这与宿主免疫系统的状态有很大关系。 随着人口老龄化，迫切需要了解宿主的年龄和性别如何影响。 年龄特异性促炎免疫系统改变对合成材料的免疫反应 这项工作的目标是确定免疫系统和目标中的关键生物因素。 这些具有免疫调节合成材料，可用于老年人群的组织再生。 总体假设是，老年免疫失调对效应物状态的化合物 对合成材料的不良反应使用先前描述的慢性非纤维化支架。 愈合伤口小鼠模型，结合测序技术和表型分析，进行实验 K99 阶段将阐明老化 FBR 中的细胞间通信网络（目标 1）以及 在整个生命周期中，先天性和适应性免疫对合成材料的反应会因性别而发生变化（目标 2）。 独立研究阶段（R00），我们将设计多级合成材料系统来控制 组织工程中失调的老年免疫反应是开发新的免疫调节生物材料的关键。 对于解决 FBR 以减少不必要的种植体相关并发症至关重要。 将提供掌握新技术方法的培训机会，使候选人做好准备 成为顶级研究机构的首席研究员，研究免疫控制的界面 伤口愈合和衰老到基于合成生物材料的疗法。