NIDCR Individual Predoctoral Dental Scientist Fellowship

NIDCR 个人博士前牙科科学家奖学金

• 批准号: 8963303
• 负责人: Elizabeth Razdolsky Michalczyk
• 金额: $ 4.89万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-16 至 2018-07-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8963303
• 关键词: Affect; Albumins; Architecture; Attention; Binding; Biological Assay; Biological Process; Blood Vessels; Blood capillaries; Cell Culture Techniques; Cell Proliferation; Cicatrix; Collagen; Complex; Connective Tissue; Dental; Dermal; Endogenous Factors; Endothelial Cells; Ensure; Equilibrium; Evaluation; Extracellular Matrix; Fellowship; Fibroblasts; Fibrosis; Future; Goals; Growth; Healed; Hemostatic Agents; Hemostatic function; Heparin; In Vitro; Indirect Immunofluorescence; Individual; Inflammation; Inflammatory; Knowledge; Light; Lipoproteins; Low-Density Lipoproteins; Malignant Neoplasms; Mechanics; Mus; National Institute of Dental and Craniofacial Research; Natural regeneration; Outcome; PECAM1 gene; Phase; Play; Process; Regenerative Medicine; Regulation; Resolution; Role; Scientist; Sirius Red F3B; Staging; Staining method; Stains; Techniques; Therapeutic; Time; Tissues; Width; Wild Type Mouse; Work; Wound Healing; angiogenesis; capillary; cell motility; cell type; effective therapy; gain of function; healing; improved; in vivo; in vivo Model; insight; pigment epithelium-derived factor; pigment epithelium-derived factor receptor; pre-doctoral; public health relevance; receptor; repaired; research study; response; tissue regeneration; tumorigenesis; vessel regression; wound

DESCRIPTION (provided by applicant): Wound healing is a complex biological process that requires coordination among multiple cell types and the dynamic extracellular matrix (ECM) microenvironment in four sequential phases: hemostasis, inflammation, proliferation, and remodeling. Although the hemostatic, inflammatory, and to some extent the proliferative phases of wound healing have been well studied, the regulation of the remodeling phase has received less attention. In the remodeling phase, the angiogenic process is complete and anti-angiogenic mechanisms play a key role in removing unnecessary vessels. Vessel regression occurs simultaneously with ECM remodeling, a process that reorganizes and reinforces matrix components to achieve mechanical strength. In most wounds, the end result of wound healing is scar formation, as the ECM never fully returns to normal architecture. Our long term goal is to understand the factors that regulate wound resolution and scar formation. Preliminary studies in our lab demonstrate that pigment epithelium-derived factor (PEDF) is an important endogenous factor that regulates vascular regression in remodeling wounds. Recent studies suggest that PEDF may also have significant interactions with cell types other than endothelial cells (EC), including fibroblasts. Moreover, the effect of PEDF may be influenced by its binding to ECM molecules such as collagen I, collagen III, and heparin. The current proposal will explore the mechanisms by which PEDF influences wound vasculature and scar formation. The central hypothesis of this proposal is that PEDF works through various ECM binding partners to both regulate vessel regression and scar formation during healing. The specific aims of this study are 1) to determine the influence of PEDF on wound angiogenesis and scar formation, 2) to analyze the distribution of PEDF receptors in the wound, and 3) to investigate the specific functional interactions between PEDF and its ECM binding partners in wounds. Aim 1 will involve in vivo studies of wound healing in PEDF-/- mice to determine PEDF's function as an anti-angiogenic and ECM remodeling factor. In Aim 2, immunohistochemical and indirect immunofluorescence studies will localize known PEDF receptors to major cell types that are involved in wound healing. Aim 3 will involve gain-of-function studies utilizing ECM-PEDF complexes. These studies will determine the synergistic effect of ECM bound PEDF on wound healing outcomes, including blood vessel growth and regression, ECM maturation, scar formation, and wound breaking strength. These experiments will provide insight into the mechanisms that regulate the remodeling phase of dermal wound healing, and may suggest future therapeutic options for tissue regeneration, fibrosis and cancer.

描述（由申请人提供）：伤口愈合是一个复杂的生物学过程，需要多种细胞类型和动态细胞外基质（ECM）微环境在四个连续阶段进行协调：止血、炎症、增殖和重塑。虽然止血，炎症，并在一定程度上的伤口愈合的增殖阶段已经得到了很好的研究，重塑阶段的调节受到较少的关注。在重塑阶段，血管生成过程是完整的，抗血管生成机制在去除不必要的血管中起关键作用。血管退化与ECM重塑同时发生，ECM重塑是一个重组和强化基质成分以获得机械强度的过程。在大多数伤口中，伤口愈合的最终结果是瘢痕形成，因为ECM永远不会完全恢复正常结构。我们的长期目标是了解调节伤口愈合和瘢痕形成的因素。我们实验室的初步研究表明，色素上皮衍生因子（PEDF）是一种重要的内源性因子，调节重塑伤口中的血管消退。最近的研究表明，PEDF也可能与内皮细胞（EC）以外的细胞类型（包括成纤维细胞）有显着的相互作用。此外，PEDF的作用可能受到其与ECM分子如胶原蛋白I、胶原蛋白III和肝素的结合的影响。目前的建议将探讨PEDF影响伤口血管和瘢痕形成的机制。该建议的中心假设是PEDF通过各种ECM结合伴侣起作用，以调节愈合期间的血管消退和瘢痕形成。本研究的具体目的是：1）确定PEDF对伤口血管生成和瘢痕形成的影响，2）分析PEDF受体在伤口中的分布，3）研究PEDF及其ECM结合伴侣在伤口中的特异性功能相互作用。目的1将涉及在体内研究PEDF-/-小鼠的伤口愈合，以确定PEDF的功能，作为一种抗血管生成和ECM重塑因子。在目标2中，免疫组织化学和间接免疫荧光研究将已知的PEDF受体定位于参与伤口愈合的主要细胞类型。目标3将涉及利用ECM-PEDF复合物的功能获得研究。这些研究将确定ECM结合的PEDF对伤口愈合结果的协同作用，包括血管生长和消退、ECM成熟、瘢痕形成和伤口断裂强度。这些实验将提供对调节皮肤伤口愈合的重塑阶段的机制的深入了解，并可能为组织再生，纤维化和癌症提供未来的治疗选择。