CD44 MEDIATED CATABOLISM OF HYALURONAN BY CHONDROCYTES

描述（改编自申请人摘要）：退化过程 在骨关节炎中涉及软骨细胞代谢的变化， 导致细胞外基质，特别是蛋白聚糖（PG）的损失， 导致组织疲劳最终导致关节衰竭海纳百川（HA）是一个关键的球员， 在组织和保留PG在软骨，但鲜为人知的是， 大分子的周转和催化。在过去的四年里， 在此期间，研究人员已经表明：（1）HA的内化是 由CD-44介导;（2）内化的HA在溶酶体中降解;（3）IL-1和 类似的试剂增加CD-44表达、HA内化以及HA和PG 从软骨基质中损失;和（4）CD-44表达增加， 骨关节炎软骨下一次筹资中要解决的问题 细胞摄取是否是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质。的 提出了以下具体目的：（1）抑制溶酶体相关酶 （2）表达突变CD-44同种型， 缺陷，从而抑制HA catalysts;和（3），以确定对 来自溶酶体透明质酸酶（HYAL-2）过表达的HA催化剂。

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).