CD44 MEDIATED CATABOLISM OF HYALURONAN BY CHONDROCYTES

CD44 介导软骨细胞对透明质酸的分解代谢

• 批准号: 6375011
• 负责人: Warren Knudson
• 金额: $ 25.87万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6375011
• 关键词: CD44 molecule; antisense nucleic acid; articular cartilage; biotransformation; chondrocytes; enzyme activity; human tissue; hyaluronate; hyaluronidase; immunocytochemistry; in situ hybridization; osteoarthritis; polymerase chain reaction; protein degradation; protein isoforms; receptor binding; receptor expression; western blottings

DESCRIPTION (Adapted from the Applicant's Abstract): The degenerative process in osteoarthritis involves changes in the metabolism of the chondrocytes and results in loss of extracellular matrix, especially proteoglycans (PG), leading to tissue fatigue and eventually joint failure. Hyaluronan (HA) is a key player in organizing and retaining PG in the cartilage, but little is known about this macromolecule's turnover and catabolism. During the last four year funding period, the investigators have shown that: (1) internalization of HA is mediated by CD-44; (2) internalized HA is degraded in lysosomes; (3) IL-1 and similar agents increase CD-44 expression, HA internalization, and HA and PG loss from the cartilage matrix; and (4) CD-44 expression is increased in osteoarthritic cartilage. The questions to be addressed in the next funding period are whether cellular uptake is the major catabolic pathway for HA and whether CD-44 is the only, or a major mediator of HA internalization. The following Specific Aims are proposed: (1) to inhibit lysosomal enzymes related to HA catabolism; (2) to express mutant CD-44 isoforms that are internalization defective and thus inhibit HA catabolism; and (3) to determine the effects on HA catabolism from overexpression of lysosomal hyaluronidase (HYAL-2).

描述（改编自申请人的摘要）：退化过程 骨关节炎涉及软骨细胞代谢的变化 导致细胞外基质，尤其是蛋白聚糖（PG）的损失，导致 导致组织疲劳并最终导致关节衰竭。透明质酸 (HA) 是关键角色 在软骨中组织和保留 PG，但对此知之甚少 大分子的周转和分解代谢。在过去四年的资助中 在此期间，研究人员表明：（1）HA的内化是 由 CD-44 介导； (2)内化的HA在溶酶体中被降解； (3) IL-1和 相似的药物可增加 CD-44 表达、HA 内化以及 HA 和 PG 软骨基质损失； (4) CD-44表达增加 骨关节炎软骨。下一步融资需要解决的问题 细胞摄取是否是HA的主要分解代谢途径和 CD-44 是否是 HA 内化的唯一介质或主要介质。这 提出以下具体目标： (1) 抑制溶酶体相关酶 HA 分解代谢； (2) 表达内化的突变CD-44亚型 有缺陷，从而抑制 HA 分解代谢； (3) 确定对的影响 溶酶体透明质酸酶 (HYAL-2) 过度表达导致的 HA 分解代谢。