Experimental Model For Pressure Ulcers In Human Skin: The Role of Aging and ECM

人类皮肤压疮的实验模型：衰老和 ECM 的作用

• 批准号: 7385171
• 负责人: Marjana Tomic-Canic
• 金额: $ 17.94万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385171
• 关键词: Address; Affect; Age; Aging; Apoptosis; Beds; Behavior; Binding; Biological; Biology; Biomechanics; Biopsy; Body Weight; Caring; Cartilage; Cause of Death; Cell physiology; Cellular Morphology; Cellular biology; Characteristics; Clinical; Clinical Trials; Collagen; Coupled; Cytoskeleton; Data; Decubitus ulcer; Deterioration; Development; Disease; Documentation; Elastin; Elderly; Evaluation; Event; Experimental Models; Extracellular Matrix; Federal Government; Fibronectins; Future; Goals; Growth Factor; Guidelines; Healthcare Systems; Hospitalization; Hospitals; Hour; Human; Immunohistochemistry; Impaired wound healing; In Vitro; Individual; Inflammatory; Integrins; Integumentary system; Knowledge; Laboratories; Lead; Life; MAP Kinase Gene; Matrix Metalloproteinases; Measures; Mechanics; Modality; Modeling; Molecular; Molecular Biology Techniques; Morbidity - disease rate; Morphology; Nursing Homes; PTK2 gene; Pain; Pathogenesis; Patients; Polymerase Chain Reaction; Population; Prevention; Process; Procollagen; Production; Property; Randomized Clinical Trials; Research; Risk; Risk Assessment; Role; Sampling; Signal Transduction; Skin; Skin Aging; Skin Tissue; Source; Specimen; Spinal cord injury; Staging; Standards of Weights and Measures; Stress; System; Techniques; Tenascin; Tensile Strength; Testing; Therapeutic; Time; Tissue Model; Tissues; Ulcer; United States Food and Drug Administration; Western Blotting; age group; age related; base; cost; cytokine; design; experience; in vivo; middle age; model development; mortality; novel therapeutics; older patient; pre-clinical; pressure; research clinical testing; response; therapeutic target

DESCRIPTION (provided by applicant): Our goal is to develop an in vitro experimental model to study skin tissue changes that lead to impaired healing and pressure ulcers in elderly. This study will determine the age-related changes in the extracellular matrix (ECM composition, organization and turnover) in human skin and how these changes contribute to its altered mechanical, cellular and molecular properties. Furthermore, we will determine how compressive stress (pressure) affects these mechanical, cellular and molecular properties. A pressure ulcer is defined as a break in the integument usually caused by continuous pressure to the skin. It is estimated that 2.5 million pressure ulcers require treatment annually in the hospital setting, primarily targeting the elderly population, with total annual costs estimated at $2.2 to $3.6 billion. This does not include pain, suffering and other morbidities associated with pressure ulcers. Currently, there is no FDA approved therapy determined in randomized clinical trials for efficacy for pressure ulcers and no experimental model. Therefore, we aim to develop an experimental model to study changes that lead to development and impaired healing in pressure ulcers. In this proposal, we will use our Mechanical Explant Test System (METS) to compressively load (stress) human skin explants and determine time and load magnitude that generates pathogenic changes in the ECM, mechanical properties, cellular processes that will contribute to impaired wound healing and development of pressure ulcers. Furthermore, we will determine age related changes that will contribute to development of pressure ulcers using skin of young (25-35 years old), middle aged (40-55 years old) and elderly individuals (60-75 years old).The following parameters will be measured in skin specimens in the absence or presence of compressive load: 1) extra cellular matrix (ECM) properties (tenascin, fibronectin, elastin, procollagen, collagen, matrix metalloproteinases (MMP)) and its signaling (integrins, FAK and MAPK); 2) mechanical properties of the skin (tensile strength); 3) cellular morphology/biology (proliferation, apoptosis, and growth factor/cytokine production) using biomechanical testing and standard molecular biology techniques (immunohistochemistry, Western blots, real-time PCR). Our long-term goal is to eliminate stage IV pressure ulcers and decrease morbidity, mortality and suffering related to pressure ulcers among the elderly population. The experimental approach proposed in this application will provide us with the opportunity to identify changes that lead to pressure ulcers in elderly, an ultimate first step towards the development of novel therapeutic modalities. Developing an experimental model to study mechanisms that lead to bed sores (pressure ulcers) in elderly human skin is the first step towards identification of the cause (pathogenesis) of pressure ulcers. Currently, there is neither an adequate experimental model nor an FDA approved therapy for these ulcers, thus our research proposed will have a high impact in future development of potential therapy for treatment of this devastating disease. An experimental model for pressure ulcers will not only provide an understanding of the underlying mechanisms of pathogenesis, but also allow for pre- clinical testing of potential therapeutic modalities.

描述（由申请人提供）：我们的目标是开发一种体外实验模型来研究皮肤组织变化，从而导致老年人的愈合和压力溃疡受损。这项研究将确定人皮肤中与年龄相关的细胞外基质（ECM组成，组织和周转）的变化，以及这些变化如何促进其机械，细胞和分子特性的改变。此外，我们将确定压缩应力（压力）如何影响这些机械，细胞和分子特性。压溃疡定义为通常是由皮肤连续压力引起的外皮的破裂。据估计，250万个压力溃疡每年在医院环境中需要治疗，主要针对老年人，总年度成本估计为2.2至36亿美元。这不包括与压溃疡有关的疼痛，痛苦和其他病因。目前，在随机临床试验中尚无FDA批准的治疗，以实现压力溃疡的功效和实验模型。因此，我们旨在开发一个实验模型，以研究导致压力溃疡中发展和愈合受损的变化。在此提案中，我们将使用机械外植体测试系统（METS）来压缩（压力）人皮外植体，并确定时间和负载幅度，从而在ECM，机械性能，机械性能，细胞过程中产生致病性变化，这将导致压力溃疡的伤口愈合和发育受损。此外，我们将确定与年龄相关的变化，这将有助于使用年轻人（25​​-35岁），中年（40-55岁）和老年人（60-75岁）（60-75岁）的皮肤发展压力溃疡的发展。以下参数将在不存在或存在压缩载荷的皮肤中在皮肤中测量额外的细胞（1）额外的纤维矩阵（ecm ecmix（ecm）（ecm ecmix）（ecm incropin），胶原蛋白酶（MMP）及其信号传导（整合素，FAK和MAPK）； 2）皮肤的机械性能（拉伸强度）； 3）使用生物力学测试和标准分子生物学技术（免疫组织化学，蛋白质印迹，实时PCR）使用细胞形态/生物学（增殖，凋亡和生长因子/细胞因子产生）。我们的长期目标是消除IV期压力溃疡，并降低与老年人口中压力溃疡有关的发病率，死亡率和苦难。本应用程序中提出的实验方法将为我们提供确定导致老年人压力溃疡的变化的机会，这是朝着新的治疗方式发展的最终第一步。开发一个实验模型来研究导致老年人皮肤床疮（压疮）的机制是迈向识别压力溃疡原因（发病机理）的第一步。当前，这些溃疡既没有足够的实验模型，也没有FDA批准的疗法，因此我们提出的研究将对未来的潜在治疗治疗这种毁灭性疾病产生巨大影响。压力溃疡的实验模型不仅可以理解发病机理的潜在机制，而且还可以预先对潜在治疗方式进行临床测试。