Collagenase degradation in extracellular matrix in aging

描述（由申请人提供）：人体皮肤，像所有其他器官一样，会随着时间的推移而发生变化。在衰老的人类皮肤中，真皮结缔组织结构经历了逐步退化，这损害了皮肤功能，导致皮肤变得薄而脆弱。老化的皮肤容易擦伤。伤口愈合缓慢且不完整，进一步削弱了皮肤。皮肤的脆弱很大程度上是由于纤维胶原蛋白的结构和组织的不可逆转的恶化，纤维胶原蛋白是皮肤中最丰富的结构蛋白。母体提案和本补充修订的长期目标是描述在人类皮肤衰老过程中发生的胶原原纤维结构和功能恶化的机制。根据我们的初步数据，我们假设皮肤老化开始于相对年轻的年龄，这是由基质金属蛋白酶-1 （MMP-1）催化的胶原蛋白裂解引起的部分降解胶原蛋白的逐渐积累造成的。这种胶原蛋白的分解改变了真皮细胞外基质和成纤维细胞之间的相互作用，成纤维细胞产生、组织并直接接触细胞外基质。胶原断裂的影响是降低成纤维细胞和细胞外基质之间施加的动态机械张力。机械张力降低改变成纤维细胞功能；诱导MMP-1表达，降低胶原蛋白生成，从而导致皮肤结缔组织进一步恶化。为了直接验证这一假设，我们培育了转基因小鼠，它们在皮肤中组成性地表达高水平的MMP-1。为了支持我们的假设，这些小鼠的皮肤结缔组织经历了快速恶化，这与在衰老的人类皮肤中观察到的情况相似。本补充修订申请建议利用新创建的皮肤结缔组织衰老小鼠模型来研究mmp -1介导的胶原断裂在衰老过程中改变成纤维细胞功能的分子机制。

DESCRIPTION (provided by applicant): Human skin, like all other organs, undergoes alterations as a consequence of the passage of time. In aged human skin, the dermal connective tissue architecture undergoes progressive degradation, which impairs skin function and causes skin to become thin and fragile. Aged skin bruises easily. Wound healing is slow and incomplete, further weakening the skin. Skin fragility largely results from irreversible deterioration of the structure and organization of fibrillar collagen, the most abundant structural protein in skin. The long-term goal of the parent proposal and this supplemental revision is to delineate mechanisms that are responsible for structural and functional deterioration of collagen fibrils that occur during human skin aging. Based on our preliminary data, we hypothesize that skin aging begins at a relatively young age brought about by gradual accumulation of partially degraded collagen, which results from matrix metalloproteinase-1 (MMP-1)-catalyzed collagen cleavage. This collagen breakdown alters interactions between the dermal extracellular matrix and fibroblasts, which produce, organize and directly contact the extracellular matrix. The impact of broken collagen is to reduce dynamic mechanical tension exerted between fibroblasts and the extracellular matrix. Reduced mechanical tension alters fibroblast function; inducing MMP-1 expression and lowering collagen production, thereby causing further deterioration of skin connective tissue. To directly test this hypothesis, we have generated transgenic mice that constitutively express high levels of MMP-1 in skin. In support of our hypothesis, skin connective tissue in these mice undergoes rapid deterioration, which resembles that observed in aged human skin. This supplemental revision application proposes to utilize this newly created mouse model of skin connective aging to investigate molecular mechanisms by which MMP-1-mediated collagen fragmentation alters fibroblast function during the aging process. PUBLIC HEALTH RELEVANCE: The long-term goal of the parent proposal and this supplemental revision is to delineate mechanisms that are responsible for structural and functional deterioration of skin connective tissue, which occurs during human skin aging. This age-related degradation of skin causes skin to become thin and fragile. Aged skin bruises easily and heals poorly. As the United States population ages, the deleterious impact of aging on skin function is a rising, significant health concern.