Hyaluronan and CD44 are Novel Targets for Acute Lung injury

透明质酸和 CD44 是急性肺损伤的新靶点

• 批准号: 8094206
• 负责人: Patrick A Singleton
• 金额: $ 39万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8094206
• 关键词: Actins; Acute Lung Injury; Antibodies; Blocking Antibodies; Blood Vessels; CD44 gene; Caveolins; Cell Surface Receptors; Cell physiology; Cells; Critical Illness; Cytoskeletal Modeling; DNA Sequence Rearrangement; Data; Disease; Dynamin 2; Endothelial Cells; Endothelium; Enzymes; Extracellular Matrix; Extravasation; Family; Guanosine Triphosphate Phosphohydrolases; Human; Hyaluronan; Hyaluronidase; Inflammatory; Intervention; Ligation; Liquid substance; Lung; Mediating; Modality; Molecular Weight; Morbidity - disease rate; Pathway interactions; Patients; Process; Protein Isoforms; Protein-Serine-Threonine Kinases; Proteins; Publishing; Regulation; Rho-associated kinase; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Stress Fibers; Structure; Techniques; Technology; Therapeutic; Variant; Vascular Endothelial Cell; angiogenesis; caveolin 1; design; inhibitor/antagonist; insight; kinase inhibitor; lung injury; mortality; nanocarrier; novel; novel therapeutics; public health relevance

DESCRIPTION (provided by applicant): Therapeutic strategies for acute lung injury (ALI), a major cause of morbidity and mortality in critically ill patients, are extremely limited. A defining feature of ALI and a target for intervention is the disruption of the lung vascular endothelial cell (EC) barrier which results in leakage of fluid, protein and cells into the airspaces of the lungs. Our novel studies indicate that the extracellular matrix component, hyaluronan (HA), and its cell surface receptor family, CD44, are important in normal EC function and angiogenesis. We have demonstrated that the ligation of the CD44 isoform, CD44s (standard form) by high molecular weight HA (HMW-HA) results in Rac1-dependent cortical actin formation and EC barrier enhancement. In contrast, low molecular weight HA ((LMW-HA), produced in pathological states by hyaluronidase enzymes) occupies CD44 variant 10 (CD44v10) and mediates RhoA-dependent actin stress fiber formation and EC barrier disruption. Therefore, enhancing the effects of HMW-HA/CD44s signaling pathways and diminishing the effects of LMW-HA/CD44v10 signaling may provide a novel therapeutic strategy for ALI via enhancing pulmonary vascular integrity. Specific Aim #1 will expand our published and preliminary data by determining HMW-HA/CD44s regulation of EC barrier function by specialized structures called caveolin-enriched microdomains (CEM) containing caveolin-1 and dynamin 2. In Specific Aim #2, we will determine HMW-HA-mediated protection from pulmonary EC barrier disruption through inhibition of RhoA GTPase and activation of Rac1 GTPase. Finally, Specific Aim #3 will employ therapeutic strategies designed to further validate HA/CD44 regulation of vascular integrity (CD44v10-specific blocking antibodies, hyaluronidase and Rho Kinase inhibitors, siRNA) using ACE antibody-directed nanocarrier technologies to target the pulmonary endothelium. These studies will yield novel mechanistic insights into HMW- HA's protection from ALI-associated pathobiology and inflammatory lung injury as well as provide novel therapeutic strategies to reduce ALI-mediated lung injury. PUBLIC HEALTH RELEVANCE: Therapeutic strategies for acute lung injury (ALI), a major cause of morbidity and mortality in critically ill patients, are extremely limited. We are examining the potential use of high molecular weight hyaluronan (HMW-HA), a substance found naturally in the body, to treat ALI through enhancement of vascular integrity. Our studies will yield novel mechanistic insights into HMW-HA's protection from ALI-associated disease processes as well as provide novel treatment modalities to reduce ALI-mediated lung injury.

描述（由申请人提供）：急性肺损伤（ALI）是危重患者发病和死亡的主要原因，其治疗策略极其有限。 ALI 的一个明确特征和干预目标是肺血管内皮细胞 (EC) 屏障的破坏，导致液体、蛋白质和细胞渗漏到肺的气腔中。我们的新研究表明，细胞外基质成分透明质酸 (HA) 及其细胞表面受体家族 CD44 对于正常 EC 功能和血管生成非常重要。我们已经证明，高分子量 HA (HMW-HA) 连接 CD44 同工型 CD44（标准型）会导致 Rac1 依赖性皮质肌动蛋白形成和 EC 屏障增强。相比之下，低分子量 HA（(LMW-HA)，在病理状态下由透明质酸酶产生）占据 CD44 变体 10 (CD44v10)，并介导 RhoA 依赖性肌动蛋白应力纤维形成和 EC 屏障破坏。因此，增强HMW-HA/CD44s信号通路的作用并减弱LMW-HA/CD44v10信号通路的作用可能为通过增强肺血管完整性来治疗ALI提供新的治疗策略。具体目标#1将通过确定HMW-HA/CD44通过包含caveolin-1和dynamin 2的称为caveolin富集微域(CEM)的特殊结构对EC屏障功能的调节来扩展我们已发表的初步数据。在具体目标#2中，我们将通过抑制RhoA GTPase和激活Rac1来确定HMW-HA介导的肺EC屏障破坏保护作用 GTP 酶。最后，具体目标#3将采用旨在进一步验证HA/CD44对血管完整性的调节（CD44v10特异性阻断抗体、透明质酸酶和Rho激酶抑制剂、siRNA）的治疗策略，使用ACE抗体导向的纳米载体技术来靶向肺内皮。这些研究将为 HMW-HA 预防 ALI 相关病理学和炎症性肺损伤提供新的机制见解，并提供新的治疗策略来减少 ALI 介导的肺损伤。 公共卫生相关性：急性肺损伤（ALI）是危重患者发病和死亡的主要原因，其治疗策略极其有限。我们正在研究高分子量透明质酸 (HMW-HA)（一种体内天然存在的物质）的潜在用途，通过增强血管完整性来治疗 ALI。我们的研究将为 HMW-HA 对 ALI 相关疾病过程的保护提供新的机制见解，并提供新的治疗方式来减少 ALI 介导的肺损伤。