SERUM AMYLOID P AND DERMAL WOUND FIBROSIS

血清淀粉样蛋白 P 与真皮伤口纤维化

• 批准号: 7659827
• 负责人: OLUYINKA OLUROTIMI OLUTOYE
• 金额: $ 21.58万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659827
• 关键词: Affect; Amyloid; Animal Model; Area; Back; Bleomycin; Blood; Buffers; Cardiac; Cells; Cicatrix; Collagen; Complex; Data; Dermal; Development; Emotional; Environment; Enzyme-Linked Immunosorbent Assay; Family suidae; Female; Fibroblasts; Fibrosis; Financial cost; Harvest; Healed; Heart; Histologic; Hypertrophic Cicatrix; In Vitro; Individual; Injection of therapeutic agent; Intraperitoneal Injections; Intravenous; Ischemia; Keloid; Left; Lesion; Lung; Modality; Modeling; Molecular Analysis; Morbidity - disease rate; Mus; Muscle; Myofibroblast; Organ; Peripheral Blood Mononuclear Cell; Plasma; Prevention; Process; Proteins; Pulmonary Fibrosis; Rattus; Recruitment Activity; Reperfusion Therapy; Research; Role; Route; Saline; Serum; Serum Proteins; Serum-Free Culture Media; Skin; Societies; Testing; Therapeutic; Tissues; Western Blotting; Wound Healing; base; design; disability; healing; high risk; in vivo; intradermal injection; intraperitoneal; loss of function; monocyte; mouse model; prevent; public health relevance; response; wound

DESCRIPTION (provided by applicant): Scarring and fibrosis is accompanied by significant morbidity and loss of function. In dermal wounds and fibrotic lesions, a subset of circulating monocytes are recruited to the wound and differentiate into fibroblast-like cells called fibrocytes. A serum protein, serum amyloid P (SAP), can prevent this differentiation in vitro. In vivo, systemic administration of SAP reduced fibrosis in rat and mouse models of bleomycin-induced pulmonary fibrosis and in a murine ischemia-reperfusion model of cardiac fibrosis. We found that systemic administration or local injections of SAP caused delayed wound contraction and healing, and decreased myofibroblast content in murine dermal wounds. Using the female red Duroc pig (FRDP) model of hypertrophic scarring, we have preliminary data indicating that local injection of SAP into deep dermal wounds appears to reduce scarring and the collagen content of these wounds. Based on these observations, we propose to evaluate the role of SAP in wound fibrosis. The key hypothesis of this study is that SAP reduces the fibrotic response in an animal model of hypertrophic scar. To test this hypothesis, we propose the following specific aims: 1: Determine if FRDPs form excessive scars due to either abnormally low serum SAP levels or an abnormal response of fibrocyte precursors to SAP. FRDP serum SAP levels, the sera's ability to inhibit fibrocyte differentiation, and the rate of fibrocyte differentiation by FRDP monocytes will be compared with control Yorkshire pigs. 2. Characterize the effect of SAP on the dermal healing response of FRDP. The effect of intradermal injection of SAP on the healing of deep wounds on FRDP will be assessed by histological, immunohistochemical and molecular analysis of the wounds. 3: Determine the effects of different routes of administration of SAP on the wound healing response. The effect of systemic and local administration of SAP on wound healing will be compared. This highly focused study will evaluate the effect of this serum protein on the complex wound healing process. If our hypothesis proves to be correct, the impact would be substantial and significant, as we might be able to use SAP to prevent excessive scarring not only in hypertrophic scars and keloids but other fibrotic skin conditions and fibrosis in general. PUBLIC HEALTH RELEVANCE: Scar formation in the skin or internal organs can result in loss of function or severe disfigurement with a substantial emotional and financial cost to the individual and society at large. Modalities to treat or prevent scar formation would help reduce the disability resulting from these conditions. This project will evaluate the effect of a naturally occurring protein in the prevention of excessive scarring. Findings of this study would impact our treatment and/or prevention of scarring, be it of the skin, muscle or internal organs.

描述（由申请人提供）：疤痕和纤维化伴随着明显的发病率和功能丧失。在皮肤伤口和纤维化病变中，将循环单核细胞的一部分募集到伤口中，并分化成称为纤维细胞的成纤维细胞样细胞。血清蛋白血清淀粉样蛋白P（SAP）可以在体外防止这种分化。在体内，SAP的全身施用降低了博来霉素诱导的肺纤维化的大鼠和小鼠模型，以及心脏纤维化的鼠缺血 - 再灌注模型。我们发现，全身给药或局部注射SAP导致伤口收缩和愈合延迟，并减少了鼠皮肤伤口中的肌纤维细胞含量。使用肥厚性疤痕的雌性红色杜罗克猪（FRDP）模型，我们有初步数据表明，将SAP局部注射到深皮真皮伤口中似乎会减少疤痕和这些伤口的胶原蛋白含量。基于这些观察结果，我们建议评估SAP在伤口纤维化中的作用。这项研究的关键假设是SAP降低了肥厚疤痕动物模型中的纤维化反应。为了检验这一假设，我们提出以下特定目的：1：确定FRDP由于血清SAP的异常低或纤维细胞前体对SAP的异常反应而导致过度疤痕。 FRDP血清SAP水平，血清抑制纤维细胞分化的能力以及FRDP单核细胞的纤维细胞分化速率将与对照约克郡猪进行比较。 2。表征SAP对FRDP真皮愈合反应的影响。皮内注射SAP对深伤对FRDP的愈合的影响将通过对伤口的组织学，免疫组织化学和分子分析来评估。 3：确定不同的SAP给药途径对伤口愈合反应的影响。将比较系统性和局部给药SAP对伤口愈合的影响。这项高度重点的研究将评估该血清蛋白对复杂伤口愈合过程的影响。如果我们的假设被证明是正确的，那么影响将是实质性和显着的，因为我们可能能够使用SAP来防止过量的疤痕，不仅在肥厚的疤痕和乳突中，而且在其他纤维化皮肤状况和纤维化中总体上都可以防止过度疤痕。公共卫生相关性：皮肤或内部器官的疤痕形成可能会导致功能丧失或严重毁容，并为个人和整个社会带来巨大的情感和财务成本。治疗或防止形成疤痕的方式将有助于减少这些疾病导致的残疾。该项目将评估天然发生的蛋白质对预防过度疤痕的影响。这项研究的结果将影响我们的治疗和/或预防疤痕，无论是皮肤，肌肉还是内部器官。