Targeting pathological hyaluronan matrices

哮喘是一种遗传背景和免疫系统相互作用的慢性炎症性疾病 与环境因素一起引发疾病的明显表现。作为慢性病的结果 炎症，甚至在较轻微的疾病中，肺的形态也可能改变。细胞外基质 (ECM)成分，如透明质酸(HA)和蛋白多糖，沉积在粘膜下层，它是 认为这些分子的积累会损害呼吸道的生物力学特性 组织。 在肺部，ECM传统上被认为是惰性支架，只有机械的 在支持和维护组织结构方面的作用。然而，最近的研究结果表明，ECM的作用 分子比之前认为的要广泛得多。这些分子在细胞间的相互作用中发挥作用，细胞基质 相互作用、细胞增殖、细胞运动和炎症。调查人员也越来越多地 透明质酸具有多种分子大小相关的生物学功能。具体地说， 大聚合物和非常小的低聚物具有抗炎和抗血管生成作用，而中等尺寸的低聚物则具有抗炎和抗血管生成的作用 透明质酸片段具有促炎和促血管生成的特性。 我们的初步研究支持HA在哮喘发病机制和炎性细胞中的作用 招聘。我们的研究还表明，HA不仅是疾病活动的生物标志物，而且是一种 潜在的治疗药物来调节AINA/AY炎症。因此，我们假设HA是一个中心 在哮喘气道炎症和重塑的组织中的中介物，HA将 作为疾病活动性的生物标志物，低分子(MW)HA将抑制炎症和 成为治疗哮喘的有用的治疗剂。为了检验这一假设，我们提出了 遵循特定的施舍。目的1探讨透明质酸作为哮喘炎症生物标志物的作用 并确定与疾病活动性或严重性的相关性。目标2调查HA作为一种 在哮喘的路上进行治疗。目的3探讨呼吸道产生透明质酸的机制 并决定淋巴细胞与透明质酸结合的功能后果。 与项目1、2和4一起，项目3计划机械化的目标，这些目标具有明确的翻译潜力 临床哮喘护理。协同研究和专家TPPG核心为项目提供了实质性的好处 3并确保将基本发现转化为哮喘改善的总体目标的成功 病人。

Asthma is a chronic inflammatory disease in which the genetic background and the immune system interact with environmental factors to elicit overt manifestations of the disease. As a consequence of the chronic inflammation, lung morphology may become altered even in milder forms of the disease. Extracellular matrix (ECM) components such as hyaluronan (HA) and proteoglycans are deposited in the submucosa, and it is thought that the accumulation of these molecules compromises the biomechanical properties of the airway tissue. In the lung, ECM has traditionally been considered to be Inert scaffolding, having only a mechanical role in supporting and maintaining tissue structure. However, recent findings indicate that the role of ECM molecules is much broader than previously thought. These molecules play a role in cell-cell interactions, cellmatrix interactions, cell proliferation, cell locomotion and inflammation. Investigators are also increasingly aware that hyaluronan exhibits a variety of molecular size-dependent biologic functions. Specifically, the large polymers and very small oligomers are anti-inflammatory and anti-angiogenic, while intermediate-sized hyaluronan fragments take on pro-inflammatory and pro-anglogenic properties. Our preliminary studies support a role for HA In the pathogenesis of asthma and In inflammatory cell recruitment. Our studies also suggest a role for HA not only as a biomarker for disease activity but also as a potential therapeutic agent to modulate ainA/ay Inflammation. Thus, we hypothesize that HA is a central mediator in the organization of inflammation and remodeling in the asthmatic airway and that HA will be a biomarker for disease activity, and low molecular weight (MW) HA will inhibit inflammation and be a useful therapeutic agent in the treatment of asthma. To test this hypothesis we propose the following specific alms. Aim 1 Investigates the utility of HA as a biomarker of inflammation In the asthmatic ainway and determine correlation with disease activity, or severity. Aim 2 investigates the utility of HA as a therapeutic in the asthmatic ainway. Aim 3 Investigates the mechanisms of HA production by the airway smooth muscle cells (SMCs) and determines the functional consequences of lymphocytes binding to the HA. Together with Projects 1, 2, and 4, Project 3 plans mechanistic aims that have clear translational potential to clinical asthma care. The synergistic research and expert TPPG cores provide substantial benefit to Project 3 and assure success of the overall goals to translate fundamental discoveries into improvements for asthma patients.