Regeneration of periodontal structures through the recruitment of regulatory lymp

通过招募调节性淋巴管来再生牙周结构

• 批准号: 8193994
• 负责人: Andrew Jason Glowacki
• 金额: $ 3.62万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193994
• 关键词: Address; Affect; Aftercare; American; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Diseases; Autoimmune Process; Behavior; Biocompatible; Bolus Infusion; Bone Resorption; Cardiovascular Diseases; Cells; Cellular biology; Characteristics; Clinical; Complex; Data; Degenerative polyarthritis; Diabetes Mellitus; Diagnosis; Disease; Disease Progression; Dose; Drug Formulations; Effectiveness; Engineering; Environment; Equilibrium; Etiology; Excision; Experimental Models; FDA approved; Future; Gingiva; Goals; Homeostasis; Imaging Techniques; Immune; Immune response; Immunology; In Vitro; Incidence; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Interleukin-10; Intraperitoneal Injections; Investigation; Kidney Diseases; Kinetics; Lead; Leukocytes; Life; Ligaments; Ligands; Light; Link; Literature; Lung diseases; Lymphocyte Subset; Measures; Mediator of activation protein; Modeling; Mus; Natural regeneration; Nature; Nuclear; Oral health; Osteoblasts; Osteocalcin; Osteoclasts; Patients; Pattern; Peptides; Periodontal Diseases; Periodontal Pocket; Periodontitis; Periodontium; Phase; Play; Premature Birth; Prevalence; Process; Production; Property; Public Health; Publishing; Reaction; Recruitment Activity; Regulatory T-Lymphocyte; Research; Resolution; Role; Schedule; Simulate; Structure; Symptoms; Systemic infection; T-Lymphocyte Subsets; TNFSF11 gene; Temporomandibular Joint; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Tooth Loss; Up-Regulation; Vasoactive Intestinal Peptide; alveolar bone; antimicrobial; base; bone; cell motility; chemokine; controlled release; cytokine; design; effective therapy; insight; killings; mathematical model; migration; mouse model; osteogenic; particle; pathogen; premature; product development; public health relevance; receptor; regenerative; residence; response; soft tissue; tissue regeneration; tool

DESCRIPTION (provided by applicant): It is becoming clear that periodontitis is not only characterized by pathogenic infection, but even more so by a loss of immunological homeostasis. Strategies toward regenerating the periodontium without completely blocking immune responses against local and systemic infections would be ideal. Based on recent insights into regulatory T cell biology, and their absence in periodontitis, we hypothesize that the recruitment of regulatory T cells to the periodontium will resolve disease symptoms and promote a regenerative milieu. To this end, we have developed a preliminary controlled release formulation for the delivery of a regulatory T cell recruiting factor (CCL-22). In our periodontal disease mouse model, intra-periodontal pocket delivery of this formulation increased regulatory T cell migration to the periodontium and led to the amelioration of disease symptoms. To further understand the mechanisms for regulatory T cell (Treg) therapy in periodontitis and develop more clinically viable therapeutics, we purpose the following aims. Specific Aim I: Investigation into the therapeutic mechanisms of Treg recruiting formulations. Herein we will examine the kinetics of regulatory T cell migration to, and residence in, the periodontium based on our current therapeutic formulation, in an experimental model of murine periodontitis. Furthermore, we will track the expression of Treg-associated factors, pro- and anti-inflammatory mediators, as well as factors that lead to hard and soft tissue destruction, to observe how Treg presence influences their presentation in the periodontium. Finally, to test the regenerative properties of Treg-recruiting formulations, we will use a live animal imaging technique to measure alveolar bone levels before, and after, treatment. Specific Aim II: Rational design of CCL-22 microparticles engineered to autonomously produce complex release characteristics. Our data strongly suggests a therapeutic effect associated with our preliminary formulation of Treg recruiting (CCL-22) microparticles after multiple injections. To make a more clinically- desirable therapy, we propose to use new mathematical models to engineer two different formulations that produce precisely defined release behavior according to two hypothetical schedules of complex chemokine delivery. Specific Aim III: Examination of VIP as a potential mediator of CCL-22 secretion by native cells. Our preliminary data shows treatment with vasoactive intestinal peptide (VIP) up-regulates the expression of endogenous Treg recruiting chemokine CCL-22 in gingival tissues of mice. Because VIP is attractive from a product development standpoint, we will investigate the therapeutic potential of VIP both systemically and through long-lasting, controlled delivery to the periodontal pocket. PUBLIC HEALTH RELEVANCE: The research has relevance to public health as it intends to address the most pressing oral health concern today, periodontitis, affecting an estimated 78 million Americans. This disease not only leads to tooth loss, but increased incidence of cardiovascular diseases, diabetes, respiratory diseases, and premature births. Further, our approach may have relevance to other disorders as osteoarthritis of the temporo-mandibular joint.

描述（由申请人提供）：越来越清楚的是，牙周炎不仅以病原体感染为特征，而且更以免疫稳态的丧失为特征。在不完全阻断对局部和全身感染的免疫反应的情况下再生牙周组织的策略将是理想的。基于对调节性T细胞生物学的最新见解，以及它们在牙周炎中的缺失，我们假设调节性T细胞向牙周组织的募集将解决疾病症状并促进再生环境。为此，我们已经开发了一种初步的控制释放制剂，用于递送调节性T细胞募集因子（CCL-22）。在我们的牙周病小鼠模型中，该制剂的牙周袋内递送增加了调节性T细胞向牙周组织的迁移，并导致疾病症状的改善。为了进一步了解调节性T细胞（Treg）治疗牙周炎的机制，并开发更多临床可行的治疗方法，我们的目的如下。具体目标I：研究Treg募集制剂的治疗机制。在此，我们将在小鼠牙周炎的实验模型中，基于我们目前的治疗配方，研究调节性T细胞迁移到牙周组织和在牙周组织中驻留的动力学。此外，我们将跟踪Treg相关因子、促炎和抗炎介质以及导致硬组织和软组织破坏的因子的表达，以观察Treg的存在如何影响它们在牙周组织中的表达。最后，为了测试Treg募集制剂的再生特性，我们将使用活体动物成像技术来测量治疗前后的牙槽骨水平。具体目标II：合理设计CCL-22微粒，使其自动产生复合物释放特性。我们的数据强烈表明了与我们的Treg募集（CCL-22）微粒的初步制剂在多次注射后相关的治疗效果。为了制造临床上更理想的疗法，我们提出使用新的数学模型来设计两种不同的制剂，其根据复杂趋化因子递送的两种假设时间表产生精确定义的释放行为。特定目的III：检查VIP作为天然细胞分泌CCL-22的潜在介质。我们的初步数据显示，血管活性肠肽（VIP）治疗上调小鼠牙龈组织中内源性Treg募集趋化因子CCL-22的表达。因为VIP从产品开发的角度来看是有吸引力的，我们将研究VIP的治疗潜力，无论是系统的，并通过持久的，控制输送到牙周袋。 公共卫生关系：这项研究与公共卫生有关，因为它旨在解决当今最紧迫的口腔健康问题，牙周炎，影响了估计7800万美国人。这种疾病不仅会导致牙齿脱落，还会增加心血管疾病、糖尿病、呼吸系统疾病和早产的发病率。此外，我们的方法可能与其他疾病有关，如颞下颌关节骨关节炎。