Biophysical Cues and Corneal Wound Healing

生物物理线索和角膜伤口愈合

基本信息

批准号：
8041488
负责人：
CHRISTOPHER John MURPHY
金额：
$ 38.3万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8041488
关键词：
Actins Address Adhesions Affect Apoptosis Apoptotic Atomic Force Microscopy Beds Behavior Blindness Cell Culture Techniques Cells Cellular biology Characteristics Collagen Cornea Corneal Injury Crosslinker Cues Cytochalasin D Data Development Elements Engineering Environment Excision Extracellular Matrix Fibroblasts Gene Proteins Healed Hydrogels Impairment In Vitro Laboratories Lead Measures Methods Modeling Myofibroblast Oryctolagus cuniculus Outcome Pathway interactions Patients Phase Phenotype Play Process Production Property Prosthesis Research Personnel Riboflavin Role Signal Transduction Signaling Molecule Smooth Muscle Actin Staining Method Stem cells Stromal Cells Testing Therapeutic Time Tissue Engineering Visual Acuity Work Wound Healing body system cell behavior cellular engineering corneal scar crosslink experience extracellular healing improved in vivo migration prevent research study response therapeutic target wound

项目摘要

DESCRIPTION (provided by applicant): Dysregulated wound healing in the cornea can lead to corneal scars and corneal haze resulting in a loss of visual acuity. While many elements of corneal wound healing are well characterized, the biophysical attributes of the wound space and the impact of these on cellular activities critical to wound healing have not been adequately investigated. Along with soluble signaling molecules present in the extracellular milieu, biophysical cues are emerging as key factors in determining cell behaviors. We propose to quantitatively analyze the alterations in stromal topography and compliance throughout the wound healing process. Our hypothesis is that the biophysical cues in the wound space alter throughout wound healing and that these directly influence the transition of keratocytes to myofibroblasts in the corneal stromal layer. The myofibroblasts, in turn, would alter the compliance of the wound microenvironment through active contraction. Ultimately, the change in the biophysical cues in the wound bed would activate apoptotic pathways, promoting removal of the myofibroblasts and an optically clear cornea would return. Using the measured alterations in the biophysical environment as a guide, we will fabricate hydrogel substrates with similar biophysical properties (of compliance and topography) to determine the cellular consequences of these alterations on myofibroblast behavior in vitro. The information that we obtain about the cellular behaviors and gene and protein alterations could enable the therapeutic targeting of biophysical cues during wound healing. Attributes of the wound bed could be directly modulated, such as the contractile elements of the corneal stromal cells, to improve wound healing outcomes. PUBLIC HEALTH RELEVANCE: Wound healing in the cornea can lead to corneal scars and can lead to impairment or loss of vision. While many elements of corneal wound healing are well characterized, biophysical attributes of the wound space have not been adequately investigated. Along with soluble signaling molecules present in the extracellular milieu, biophysical cues are emerging as key regulators of cell behaviors. This proposal would determine the biophysical cues (specifically topography and compliance) present throughout corneal sromal wound healing. Our hypothesis is that the biophysical attributes of the wound space changes throughout the healing process and that the transition of phenotypes of the cells in the corneal stromal layer is modulated by alterations in the biophysical cues of the wound space. In addition, the myofibroblast, a central player in normal and dysregulated wound healing will modify the compliance of the wound microenvironment and thereby assist in wound repair, but also in ultimately triggering signals necessary to prevent corneal haziness. If proven true, our hypothesis would indicate that direct modulation of the biophysical properties and contractile elements of the corneal stromal cells could improve wound healing outcomes.

描述（由申请人提供）：角膜伤口愈合失调会导致角膜疤痕和角膜混浊，从而导致视力丧失。虽然角膜伤口愈合的许多要素已得到充分表征，但伤口空间的生物物理属性及其对伤口愈合至关重要的细胞活动的影响尚未得到充分研究。与细胞外环境中存在的可溶性信号分子一起，生物物理线索正在成为决定细胞行为的关键因素。我们建议定量分析整个伤口愈合过程中基质地形和顺应性的变化。我们的假设是，伤口空间中的生物物理线索在整个伤口愈合过程中发生变化，并且这些直接影响角膜基质层中角膜细胞向肌成纤维细胞的转变。肌成纤维细胞反过来会通过主动收缩改变伤口微环境的顺应性。最终，伤口床中生物物理信号的变化将激活细胞凋亡途径，促进肌成纤维细胞的去除，并且光学透明的角膜将恢复。以测量到的生物物理环境变化为指导，我们将制造具有相似生物物理特性（顺应性和形貌）的水凝胶基质，以确定这些变化对体外肌成纤维细胞行为的细胞影响。我们获得的有关细胞行为以及基因和蛋白质改变的信息可以在伤口愈合过程中实现生物物理线索的治疗目标。可以直接调节伤口床的属性，例如角膜基质细胞的收缩成分，以改善伤口愈合结果。公共卫生相关性：角膜伤口愈合可能导致角膜疤痕，并可能导致视力损伤或丧失。虽然角膜伤口愈合的许多要素已得到充分表征，但伤口空间的生物物理属性尚未得到充分研究。与细胞外环境中存在的可溶性信号分子一起，生物物理线索正在成为细胞行为的关键调节剂。该提议将确定整个角膜基质伤口愈合过程中存在的生物物理线索（特别是地形和顺应性）。我们的假设是，伤口空间的生物物理属性在整个愈合过程中发生变化，并且角膜基质层细胞表型的转变是通过伤口空间生物物理线索的改变来调节的。此外，肌成纤维细胞是正常和失调伤口愈合的核心参与者，它会改变伤口微环境的顺应性，从而有助于伤口修复，但也最终触发防止角膜浑浊所需的信号。如果被证明是正确的，我们的假设将表明直接调节角膜基质细胞的生物物理特性和收缩成分可以改善伤口愈合结果。