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”

摘要： 这项研究的主要目的是确定雅普/TAZ调节年龄相关性的分子机制。 皮肤真皮细胞外基质（ECM）稳态。 在人类皮肤中，真皮成纤维细胞负责富含胶原蛋白的细胞的产生、组织和稳态。 真皮ECM，其包括皮肤的大部分。在年轻的皮肤中，直接附着在完整的胶原纤维上， 通过细胞骨架组装所产生的机械力，成纤维细胞实现铺展结构。 在这种状态下，雅普/TAZ途径是活跃的，其保持年轻的合成代谢表型，并产生净ECM。在 老化的皮肤，破碎的胶原纤维不支持成纤维细胞附着，导致机械力/拉伸降低 雅普/TAZ功能下降。在这种状态下，成纤维细胞显示出老化的分解代谢表型，具有净ECM降解， 它是自我延续的，并创造了一个皮肤微环境，促进许多年龄的发病机制， 相关的皮肤病。 我们建议研究真皮成纤维细胞中的雅普/TAZ机械感应信号通路是一个可能的机制。 年龄相关的真皮ECM稳态的关键调节剂。这种数据驱动的假设包含以下关键概念： 真皮ECM稳态受成纤维细胞对周围ECM微环境的适应支配， 而不是细胞自主因素因此，我们认为真皮ECM稳态涉及真皮ECM的“外-内适应”， 成纤维细胞的皮肤ECM的年龄相关的状态，其中成纤维细胞包埋，这种适应是 由雅普/TAZ严格监管。 为了验证上述假设，我们最近产生了两种互补的转基因小鼠模型：1） 条件性敲除真皮成纤维细胞中的雅普/Taz，这导致新生儿真皮ECM 成熟和显着加速的时间顺序真皮ECM老化; 2）真皮老化的人源化小鼠模型 由真皮成纤维细胞中胶原降解基质金属蛋白酶-1的表达驱动。重要的是，这种模式 显示响应ECM降解的雅普/TAZ的生理失活。 为检验所述假设，提出了以下具体目标： 目的1：确定雅普/TAZ介导真皮ECM均一化的分子机制 在出生后早期和年龄老化期间 目的2：确定雅普/TAZ功能的恢复对真皮ECM稳态的影响 目的3：介导雅普/TAZ年龄相关功能衰退的门控机制 成纤维细胞“外向内适应”