Microparticles Modulating Regulatory T cells in Periodontal Disease

微粒调节牙周病中的调节性 T 细胞

• 批准号: 10285799
• 负责人: Nisarg J. Shah
• 金额: $ 14.35万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285799
• 关键词: Affect; Animal Model; Anti-Inflammatory Agents; Antigens; Applications Grants; Attenuated; Autoimmune Diseases; Bacteria; Biological; Bone Tissue; CD4 Positive T Lymphocytes; Cells; Characteristics; Chemical Structure; Chronic; Cicatrix; Clinical; Connective Tissue; Consult; Data; Development; Disease; Disease Progression; Drug Delivery Systems; Encapsulated; Environment; Exhibits; Exposure to; FOXP3 gene; Fibrosis; Fluorescence; Gingiva; Gingivitis; Glycolates; Helper-Inducer T-Lymphocyte; Homeostasis; Human; IL2RA gene; Immune; Immune response; Immunologic Memory; Immunology; Immunophenotyping; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Interferon Type II; Interleukin-10; Interleukin-17; Kinetics; Label; Lead; Lesion; Mastication; Measurement; Measures; Mediating; Mediator of activation protein; Methods; Modeling; Mus; Needles; Neutrophil Activation; Neutrophil Infiltration; Oral; Oral mucous membrane structure; Participant; Pathogenesis; Pathogenicity; Pathway interactions; Peptide Hydrolases; Periodontal Diseases; Periodontitis; Phenotype; Play; Polymers; Production; Proteins; RNA; Recurrence; Regulatory T-Lymphocyte; Research; Research Personnel; Resolution; Role; Scientist; Sirolimus; Site; Spectrum Analysis; Stimulus; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Tissue Engineering; Tissues; Tretinoin; Tumor-infiltrating immune cells; Up-Regulation; Work; alveolar bone; base; beta-Cyclodextrins; bone; controlled release; copolymer; cytokine; dietary; effector T cell; experimental study; immunoregulation; in vivo; inflammatory modulation; neutrophil; novel; pre-clinical; prevent; release factor; soft tissue

PROJECT SUMMARY Periodontal disease (PD) is chronic inflammatory disorder characterized by the infection of gingiva, connective tissue and alveolar bone. Dense immune cell infiltrates are characteristic in PD, of which T cells are key mediators of the host response and are significant participants in PD progression. Among the participating T cell subsets, regulatory T cells (Treg) have been identified in PD-affected tissue and generally function to suppress pro-inflammatory T cells. However, in chronic inflammatory lesions, Treg may lose immunoregulatory function and, instead, produce pro-inflammatory cytokines. We hypothesize that restoring Treg function will influence the immune response in PD. To test the hypothesis, the project will develop immunomodulatory microparticles to functionally stabilize Treg in periodontal tissue. The project comprises two aims – Aim 1 will optimize the synthesis of biodegradable microparticles for encapsulating immunomodulatory factors. We will measure and tune the rate of release to sustain biologically relevant concentrations for mediating immunomodulation. By measuring in vitro immunophenotypic stability and cytokine production by Treg, we will assess bioactivity of the released factors. Aim 2 will test microparticle delivery in a mouse periodontitis model. We will measure in vivo degradation and quantify the local enhancement of Treg mediated by the microparticles. We will conduct functional measurements by measuring the concentrations of associated cytokines and tissue inflammation using histomorphometry-based analysis. Overall, the experiments will evaluate the feasibility of in vivo Treg expansion and stabilization for attenuating inflammation in PD. The PI is a New Investigator with expertise in drug delivery, tissue engineering and immunology and will collaborate with the co-I, a clinician-scientist with expertise in autoimmune disease with a focus on how inflammation-induced Treg instability results in pathogenic production of inflammatory cytokines. The results from the project will assess the feasibility of microparticle-mediated modulation of inflammatory T cells in PD and lead to a R01 grant application to comprehensively characterize immunomodulation for durably controlling chronic inflammation in PD.

项目摘要 牙周病（periodontitis disease，PD）是一种慢性炎症性疾病，其特征是牙龈、结缔组织和牙周组织的感染， 组织和牙槽骨。密集的免疫细胞浸润是PD的特征，其中T细胞是关键 介导宿主反应，是PD进展的重要参与者。在参与的T 细胞亚群，调节性T细胞（Treg）已经在PD影响的组织中被鉴定，并且通常起以下作用： 抑制促炎性T细胞。然而，在慢性炎性病变中，Treg可能失去免疫调节功能， 而是产生促炎细胞因子。我们假设恢复Treg功能将 影响PD患者的免疫反应。为了验证这一假设，该项目将开发免疫调节 牙周组织中的Treg的功能稳定。该项目包括两个目标：目标1将 优化用于包封免疫调节因子的生物可降解微粒的合成。我们将 测量和调节释放速率以维持生物相关浓度， 免疫调节通过测量Treg的体外免疫表型稳定性和细胞因子产生，我们将 评估释放因子的生物活性。目的2将在小鼠牙周炎模型中测试微粒递送。 我们将测量体内降解并量化由免疫调节蛋白介导的Treg的局部增强。 微粒。我们将通过测量相关的浓度来进行功能测量。 细胞因子和组织炎症使用基于组织形态计量学的分析。总的来说，实验将 评估体内Treg扩增和稳定用于减轻PD中炎症的可行性。PI是一个 新的研究者具有药物输送，组织工程和免疫学方面的专业知识，并将与 我是一名临床科学家，擅长自身免疫性疾病，专注于炎症诱导的 Treg不稳定性导致炎性细胞因子的致病性产生。该项目的结果将 评估微粒介导的PD炎症T细胞调节的可行性，并导致R01 授予申请全面表征免疫调节，以持久控制慢性 PD炎症