Collagenase degradation in extracellular matrix in aging

描述(申请人提供)：人的皮肤，像所有其他器官一样，会随着时间的推移而发生变化。在老年人的皮肤中，真皮结缔组织结构经历了渐进性的降解，这损害了皮肤功能，导致皮肤变得薄而脆弱。老化的皮肤容易瘀伤。伤口愈合缓慢且不完全，进一步削弱皮肤。皮肤脆弱在很大程度上是由于皮肤中含量最丰富的结构蛋白--纤维状胶原的结构和组织不可逆转地恶化所致。父提案和这一补充修订的长期目标是描述在人类皮肤老化过程中导致胶原纤维结构和功能恶化的机制。根据我们的初步数据，我们假设皮肤衰老始于相对年轻的年龄，这是由于部分降解的胶原蛋白逐渐积累，这是基质金属蛋白酶-1(MMP1)催化的胶原蛋白裂解的结果。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。减少的机械张力改变成纤维细胞的功能，诱导基质金属蛋白酶-1的表达，减少胶原的产生，从而导致皮肤结缔组织的进一步恶化。为了直接验证这一假设，我们培育了转基因小鼠，这些小鼠在皮肤中结构性地表达高水平的基质金属蛋白酶-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的退化，这与在老化的人类皮肤中观察到的相似。这一补充修订应用程序建议利用这一新创建的皮肤结缔组织老化模型来研究基质金属蛋白酶-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。 公共卫生相关性：父提案和本次补充修订的长期目标是描述导致皮肤结缔组织结构和功能恶化的机制，皮肤结缔组织在人类皮肤老化过程中发生。这种与年龄相关的皮肤退化会导致皮肤变薄和脆弱。老化的皮肤容易瘀伤，愈合不好。随着美国人口老龄化，衰老对皮肤功能的有害影响是一个日益严重的健康问题。

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.