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Novel Mechanisms of Regenerative Wound Healing

伤口再生愈合的新机制

基本信息

批准号：
9331717
负责人：
Sundeep G Keswani
金额：
$ 30.7万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9331717
关键词：
Adult Affect Anti-Inflammatory Agents Anti-inflammatory Attenuated Benchmarking Biological Biology Caring Cell physiology Characteristics Cicatrix Data Dermal Diabetes Mellitus Disease Effector Cell Extracellular Matrix Fibroblasts Goals Hyaluronan Impaired wound healing Impairment In Vitro Inflammation Inflammatory Response Interleukin-10 Knockout Mice Knowledge Lead Mediating Mediator of activation protein Modeling Molecular Molecular Weight Pathway interactions Patient Care Phenotype Pregnancy Public Health Regenerative response Regulation Research Role STAT3 gene Series Signal Pathway Signal Transduction Skin Source Stimulus Surgeon Testing Tissues Transgenic Mice Wound Healing clinical practice clinical translation fetal fetal reactivity healing immunoregulation improved in utero in vivo innovation insight keratinocyte migration mouse model novel overexpression pleiotropism postnatal regenerative repaired response therapeutic development tissue repair wound

项目摘要

Project Summary Abstract Fetal wounds heal with a regenerative phenotype that is indistinguishable from surrounding skin with restored skin integrity. Compared to this benchmark, all postnatal wound healing is impaired. We can use the biologic basis of the fetal regenerative phenotype as a roadmap to recapitulate regenerative wound healing in adult skin. This would have significant impact for normal wound repair, as well as in impaired wound healing states, such as diabetes. Fetal wounds are characterized by an attenuated inflammatory response and a characteristic fibroblast-mediated ECM, that is composed of high molecular weight hyaluronan. The dermal fibroblast is a primary source of hyaluronan in fetal skin; conversely, in adult wounds, the fibroblast is the main mediator of scar formation. We hypothesize that there are cellular processes in fetal fibroblasts that regulate the regenerative phenotype, which are also present in fibroblasts resident in adult wounds but lack an appropriate stimulus. Our data suggests that interleukin-10 (IL-10) may be the initial stimulus that reactivates a regenerative phenotype in adult wounds. In addition to IL-10's accepted immuno-regulatory role, our preliminary data indicate a new mechanism for IL-10 in the fetal regenerative phenotype and that is regulation of the extracellular matrix, specifically hyaluronan synthesis. To elucidate the mechanisms by which IL-10 governs fetal regenerative healing and to determine whether activation of these same mechanisms in fibroblasts resident in adult wounds can recapitulate regenerative repair, we propose the following three aims: Aim 1: identify and characterize the effects of IL-10 on the fetal fibroblast formation of hyaluronan and elucidate a potential signaling pathway. After testing if this pathway that regulates the ECM is essential to the fetal wound healing phenotype, we can determine if IL-10 induction of hyaluronan synthesis can affect regenerative wound healing in adult wounds. Aim 2: use a series of novel transgenic mice to test if IL-10's effects are mediated via STAT3 dependent signaling in dermal fibroblasts and determine if the fibroblast is the key effector cell of IL-10's regenerative response. Aim 3: test if the IL-10 induced hyaluronan ECM is essential to enhancing cellular functions of the fibroblast and attenuating wound inflammation as part of the regenerative response. Lastly, using mouse models that are characterized by dysfunctional fibroblasts and altered wound inflammation, we will determine if IL-10 can correct these collective deficiencies and augment wound repair. For unknown reasons, the remarkable ability that we all possess to heal regeneratively in utero is lost in late gestation and instead defaults to a scarring phenotype. Completing our aims will yield fundamental insights and new knowledge into IL-10 biology and the recapitulation of fetal regenerative healing in adult wounds. This will offer significant possibilities to improve the care of patients who cope with the debilitating aspects of impaired wound healing quality and scar formation by the development of therapeutics that may have broad implications for regenerative tissue repair.

项目摘要