Transforming Growth Factor-Beta (TGF-b) Signaling in Photoaged and Chronologicall

光老化和时序中的转化生长因子-β (TGF-b) 信号转导

• 批准号: 8067000
• 负责人: GARY J FISHER
• 金额: $ 30.44万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067000
• 关键词: Accounting; Address; Age; Aging; Aging-Related Process; Binding; Biological Process; Cell Surface Receptors; Cell physiology; Cell surface; Cells; Characteristics; Collagen; Collagen Type I; Color; Complex; Connective Tissue; Data; Dermal; Dermis; Development; Disease; ECM receptor; Elasticity; Elderly; Environment; Enzymes; Epigenetic Process; Extracellular Matrix; Family; Fibroblasts; Filler; Genetic; Grant; Half-Life; Health; Human; Impaired wound healing; Impairment; Incidence; Injection of therapeutic agent; Integrin Binding; Integrins; Investigation; Knowledge; Malignant Neoplasms; Mechanics; Mediating; Metabolic; Modality; Modeling; Molecular; Morbidity - disease rate; Organ; Pathway interactions; Phenotype; Phosphotransferases; Population; Production; Property; Proteins; Proteomics; Public Health; Research; Resistance; Role; Scaffolding Protein; Shapes; Signal Transduction; Site; Skin; Skin Aging; Skin Cancer; Stress; Stretching; Structure; Testing; Thinness; Time; Tissues; Transforming Growth Factor beta; Wound Healing; age related; aged; base; cell type; driving force; extracellular; improved; in vivo; novel; public health relevance; receptor; response; skin disorder

DESCRIPTION (provided by applicant): A characteristic feature of chronological aging is cline of organ function. Manifestations of this decline in human skin include fragility, impaired wound healing, increased incidence of cancer, reduced elasticity and tone, uneven color, and increased roughness. All of these features are attributable, at least in part, to impairment of the structural integrity of skin connective tissue. The structural component of skin connective tissue is the dermal extracellular matrix (ECM), which is primarily composed of fibrillar type I collagen framework. The structure and function of this type I collagen framework is modulated through direct and indirect interactions with hundreds of additional proteins, which, like type I collagen, are primarily synthesized and secreted by dermal fibroblasts. Fibroblasts adhere to the ECM through integrins, which are a family of specific cell surface ECM receptors. ECM-fibroblast interactions inform and control both ECM and fibroblast functions via integrin attachment sites. These sites regulate function through two interrelated mechanisms: 1) conventional signal transduction, mediated by kinase cascades, and 2) mechanical force transduction, mediated by cytoskeletal machinery and intracellular scaffold proteins. During the aging process, fibrillar type I collagen is fragmented. This fragmentation deleteriously impacts skin health by directly compromising mechanical stability and by destroying ECM sites for fibroblast attachment. Our data indicate that these two factors conspire to reduce mechanical tension within fibroblasts in human skin in vivo. Reduction of mechanical tension manifests as change of fibroblast shape from "stretched" to "collapsed". Fibroblast "collapse" is significant, because a fundamental property of cells is the connection between shape and function. Based on our preliminary data, we hypothesize that fragmented ECM accumulates with aging and causes fibroblasts to "collapse", resulting in reduced ability to respond to transforming growth factor-beta (TGF-2), which is the primary driving force for ECM production. Reduced collagen production further deteriorates ECM structural integrity, leading to further fibroblast "collapse", further resistance to TGF-2, and further diminishment of collagen production. This self-perpetuating decline of ECM/fibroblast functions eventuates in thin, fragile skin, characteristically seen in the elderly. To test this hypothesis, Specific Aim 1 will investigate molecular mechanisms by which the fragmented ECM microenvironment regulates TGF-2-dependent collagen production. Specific Aim 2 will investigate the impact of increasing mechanical tension in the dermis of aged human skin, by injection of space filling material, on fibroblast shape and function. Specific Aim 3 will delineate mechanisms by which fragmented collagen matrix down-regulates type II TGF-2 receptor. Specific Aim 4 will investigate mechanisms by which type I collagen-binding integrins sense, signal, and regulate fibroblast shape/mechanical tension in response to fragmented ECM microenvironment. The proposed studies are significant because they will: 1) advance knowledge of molecular mechanisms that are responsible for age-dependent decline of human skin function, 2) provide a new paradigm for understanding the impact of age-dependent ECM alterations on tissue function, and 3) enable development of new modalities to improve the health of the elderly. The proposed studies are novel because they depart from the cellular- centric view of aging to address the role of dynamic interplay between cells and their ECM microenvironment during the aging process. PUBLIC HEALTH RELEVANCE: The primary objective of this proposal is to investigate molecular mechanisms that are responsible for reduction of type I collagen synthesis in chronologically aged human skin. Loss of type I collagen deleteriously alters the structural integrity of skin connective tissue, and thereby impairing skin function and promoting age-related skin diseases. Our findings from the initial grant demonstrate that age-related reduction of type I collagen is mediated by impairment of the TGF-2 pathway in dermal fibroblasts. This proposal builds on our previous findings and will test the hypothesis that accumulation of aged-related alterations of the structural/mechanical/functional properties of the collagenous extracellular matrix in human dermis impairs dermal fibroblast functions, including TGF-2-dependent collagen production. This hypothesis is novel because it focuses on the importance of the extracellular matrix, rather than inherent cellular deficits, as a driving force for the aging process in humans.

描述(申请人提供)：慢性衰老的一个特征是器官功能的倾斜。人类皮肤的这种衰退的表现包括脆弱、伤口愈合受损、癌症发病率增加、弹性和色泽降低、颜色不均匀以及粗糙度增加。所有这些特征至少部分归因于皮肤结缔组织结构完整性的损害。皮肤结缔组织的结构成分是真皮细胞外基质(ECM)，主要由I型胶原纤维骨架组成。这种I型胶原的结构和功能是通过与数百种额外的蛋白质直接或间接相互作用来调节的，这些蛋白质和I型胶原一样，主要由真皮成纤维细胞合成和分泌。成纤维细胞通过整合素与细胞外基质黏附，整合素是一类特殊的细胞表面细胞外基质受体。细胞外基质与成纤维细胞之间的相互作用通过整合素附着位点影响和控制细胞外基质和成纤维细胞的功能。这些位点通过两种相互关联的机制来调节功能：1)由激酶级联介导的常规信号转导；2)由细胞骨架机械和细胞内支架蛋白介导的机械力转导。在老化过程中，I型胶原纤维碎裂。这种碎裂直接影响皮肤的机械稳定性，破坏成纤维细胞附着的细胞外基质部位，从而有害地影响皮肤健康。我们的数据表明，这两个因素共同降低了体内人皮肤成纤维细胞内的机械张力。机械张力降低主要表现为成纤维细胞形态由“拉伸”变为“收缩”。成纤维细胞的“崩溃”意义重大，因为细胞的一个基本属性是形态和功能之间的联系。根据我们的初步数据，我们假设碎裂的ECM随着年龄的增长而积累，并导致成纤维细胞“崩溃”，导致对转化生长因子-β(TGF-2)的反应能力降低，而转化生长因子-β是ECM产生的主要驱动力。胶原生成的减少进一步恶化了ECM的结构完整性，导致成纤维细胞进一步“崩溃”，进一步抵抗转化生长因子-2，并进一步减少胶原的产生。这种细胞外基质/成纤维细胞功能的自持性下降最终会出现在薄而脆弱的皮肤上，这是老年人的特征。为了验证这一假设，《特定目标1》将研究碎片化的ECM微环境调节依赖于转化生长因子-2的胶原产生的分子机制。具体目的2将通过注射间隙填充材料来研究老年人皮肤真皮机械张力增加对成纤维细胞形态和功能的影响。具体目标3将描述碎裂的胶原基质下调II型转化生长因子-2受体的机制。具体目标4将研究I型胶原结合整合素感知、信号和调节成纤维细胞形状/机械张力以响应碎裂的ECM微环境的机制。拟议的研究具有重要意义，因为它们将：1)促进对导致人类皮肤功能随年龄增长而下降的分子机制的了解；2)为理解与年龄相关的细胞外基质改变对组织功能的影响提供新的范式；以及3)使新的模式得以发展，以改善老年人的健康。所提出的研究具有新颖性，因为它们脱离了以细胞为中心的衰老观点，以解决细胞及其细胞外基质微环境在衰老过程中的动态相互作用的作用。 公共卫生相关性：这项建议的主要目标是研究导致人类皮肤I型胶原合成减少的分子机制。I型胶原的丧失有害地改变了皮肤结缔组织的结构完整性，从而损害了皮肤功能，促进了与年龄相关的皮肤病。我们从最初的资助中发现，与年龄相关的I型胶原的减少是由真皮成纤维细胞中转化生长因子-2途径的损伤所介导的。这一建议建立在我们先前发现的基础上，并将检验这样一种假设，即随着年龄的增长，人真皮中胶原细胞外基质的结构/机械/功能特性的变化会损害真皮成纤维细胞的功能，包括依赖于转化生长因子-2的胶原的产生。这一假说是新颖的，因为它关注的是细胞外基质的重要性，而不是固有的细胞缺陷，作为人类衰老过程的驱动力。