CD44 MEDIATED CATABOLISM OF HYALURONAN BY CHONDROCYTES

描述(改编自申请者摘要)：退化过程 在骨关节炎中涉及软骨细胞新陈代谢的变化和 导致细胞外基质的丢失，特别是蛋白多糖(PG)，导致 导致组织疲劳并最终导致关节衰竭。透明质酸(HA)是一个关键的参与者 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。在过去的四年中，资金 在此期间，研究人员表明：(1)HA的内化是 由CD-44介导；(2)内化HA在溶酶体中降解；(3)IL-1和 类似药物可增加CD-44表达、HA内化以及HA和PG 软骨基质丢失；(4)CD-44表达增加 骨关节炎软骨。下一笔资金中需要解决的问题 细胞摄取是否是HA和HA的主要分解代谢途径 CD-44是否是HA内化的唯一或主要介体。这个 提出了以下具体目标：(1)抑制溶酶体相关酶 与HA分解代谢有关；(2)表达内化突变的CD-44亚型 有缺陷，从而抑制HA分解代谢；以及(3)确定对 溶酶体透明质酸酶(HYAL-2)过表达引起的HA分解代谢。

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).