YAP/TAZ Regulation of Extracellular Matrix Homeostasis

YAP/TAZ 细胞外基质稳态的调节

• 批准号: 10719507
• 负责人: GARY J FISHER
• 金额: $ 65.23万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719507
• 关键词: Acceleration; Affect; Aging; Applications Grants; Architecture; Atrophic; Behavior; Cells; Chronology; Clinical; Collagen; Collagen Fibril; Contusions; Cytoskeleton; Data; Dermal; Deterioration; Disease; Elderly; Extracellular Matrix; Extracellular Matrix Degradation; Fibroblasts; Goals; Growth; Homeostasis; Human; Immunity; Impairment; Individual; Interstitial Collagenase; Investigation; Life; Link; Malignant Neoplasms; Mechanics; Mediating; Modeling; Molecular; Morbidity - disease rate; Morphology; Neonatal; Pathogenesis; Pathway interactions; Phenotype; Physiological; Production; Proteins; Regulation; Risk Factors; Signal Pathway; Skin; Skin Aging; Skin Cancer; Stretching; Testing; Thinness; Transcription Coactivator; age related; aged; conditional knockout; functional decline; humanized mouse; mechanical force; mechanical properties; mechanotransduction; mouse model; novel; postnatal; resilience; response; restoration; skin disorder; wound healing

ABSTRACT: The major goal of this grant application is to determine the molecular mechanisms by which YAP/TAZ regulate age-related skin dermal extracellular matrix (ECM) homeostasis. In human skin, dermal fibroblasts are responsible for the production, organization, and homeostasis of the collagen-rich dermal ECM, which comprises the bulk of the skin. In young skin, direct attachment to intact collagen fibrils allows fibroblasts to achieve a spread architecture, through mechanical forces generated by the assembly of the cytoskeleton. In this state, the YAP/TAZ pathway is active, which maintains a youthful anabolic phenotype with net ECM production. In aged skin, fragmented collagen fibrils do not support fibroblast attachment, resulting in reduced mechanical force/stretching and a decline in YAP/TAZ function. In this state, fibroblasts display an aged catabolic phenotype, with net ECM degradation, which is self-perpetuating and creates a dermal microenvironment milieu that promotes the pathogenesis of many age- related skin diseases. We propose to investigate the hypothesis that the YAP/TAZ mechano-sensing signaling pathway in dermal fibroblasts is a critical regulator of age-related dermal ECM homeostasis. This data-driven hypothesis encompasses the key concept that dermal ECM homeostasis is governed by the adaptation of fibroblasts to the surrounding ECM microenvironment, rather than cell‐autonomous factors. Thus, we view dermal ECM homeostasis as involving “outside‐in adaptation” of dermal fibroblasts to the age‐related state of the dermal ECM, in which fibroblasts are embedded, and that this adaptation is critically regulated by YAP/TAZ. To test the above hypothesis, we have recently generated two complementary genetically modified mouse models: 1) conditional knockout of Yap/Taz in dermal fibroblasts, which results in striking impairment of both neonatal dermal ECM maturation and significantly accelerated chronological dermal ECM aging; 2) humanized mouse model of dermal aging driven by expression of collage-degrading matrix metalloproteinase-1 in dermal fibroblasts. Importantly, this model displays physiological inactivation of YAP/TAZ in response to ECM degradation. Following Specific aims are proposed to test the stated hypothesis: AIM 1: DETERMINE THE MOLECULAR MECHANISMS BY WHICH YAP/TAZ MEDIATES DERMAL ECM HOMEOSTASIS DURING EARLY POSTNATAL LIFE AND CHRONOLOGICAL AGING AIM 2: DETERMINE THE IMPACT OF RESTORATION OF YAP/TAZ FUNCTION ON DERMAL ECM HOMEOSTASIS AIM 3: INVESTIGATE MECHANISMS BY WHICH AGE-RELATED FUNCTIONAL DECLINE OF YAP/TAZ IS MEDIATED BY FIBROBLASTS “OUTSIDE-IN ADAPTION”

抽象的： 该赠款应用的主要目标是确定YAP/TAZ调节与年龄相关的分子机制 皮肤皮肤外基质（ECM）稳态。 在人皮中，皮肤成纤维细胞负责胶原蛋白丰富的生产，组织和稳态 皮肤ECM，包括大部分皮肤。在年轻的皮肤中，直接附着完整的胶原蛋白纤维允许 成纤维细胞通过细胞骨架组装产生的机械力实现扩散结构。 在这种状态下，YAP/TAZ途径是活跃的，该途径保持了ECM净生产的年轻合成代谢表型。 老化的皮肤，碎片胶原纤维不支持成纤维细胞附着，导致机械力/拉伸减少 YAP/TAZ功能下降。在这种状态下，成纤维细胞显示出年迈的分解代谢表型，净ECM降解， 这是自我延续的，并创建了真皮微环境环境，该环境促进了许多年龄的发病机理 相关的皮肤病。 我们建议研究真皮成纤维细胞中的YAP/TAZ机械感应信号通路是一个 与年龄相关的皮肤ECM稳态的关键调节剂。这个数据驱动的假设包含了关键概念 真皮ECM稳态受到成纤维细胞对周围ECM微环境的适应 比细胞自主因素。那就是，我们认为真皮ECM稳态涉及真皮的“外部适应” 成纤维细胞嵌入成纤维细胞的皮肤ECM的年龄相关状态，并且这种适应为 受YAP/TAZ严格调节。 为了检验上述假设，我们最近生成了两个完全基因修饰的小鼠模型：1） 皮肤成纤维细胞中YAP/TAZ的条件敲除，这导致两种新生儿真皮ECM的障碍 成熟和显着加速的年代皮肤ECM衰老； 2）真皮衰老的人源化小鼠模型 由皮肤成纤维细胞中胶原胶降解基质金属蛋白酶1的表达驱动。重要的是，这个模型 显示YAP/TAZ的物理灭活，以响应ECM降解。 提出了以下特定目的来检验既定假设： 目标1：确定YAP/TAZ介导皮肤ECM稳态的分子机制 在产后早期和年代老化中 目标2：确定YAP/TAZ功能对皮肤ECM稳态的恢复的影响 AIM 3：调查与年龄相关的YAP/TAZ功能下降的机制 成纤维细胞“外部适应”