Defining translational mechanisms to promote regenerative healing of chronic wounds

确定翻译机制以促进慢性伤口的再生愈合 摘要： 慢性创伤在我们的退伍军人中很常见，经常对他们的能力产生负面影响， 作为我们社会的生产性成员，实现高质量的生活，并照顾这些伤口， 他们的后遗症消耗了退伍军人健康管理局的很大一部分资源。 本提案中所述研究的最终目标是开发解决方案， 这些伤口的持久和再生愈合。老年人和/或糖尿病患者 主要风险发展困难的不愈合的伤口，糖尿病发生在退伍军人中， 是美国人口的三倍。为了有效地处理这些伤口， 了解正常的愈合过程和工程师的治疗，促进身体和 愈合组织的生化环境。在病理学上，我们对特定亚类的鉴定 人类皮肤内的细胞以及它们如何控制皮肤伤口愈合具有改善 皮肤感染和慢性伤口。 我们的长期目标是将我们对细胞和分子相互作用的理解转化为 推动皮肤修复成为慢性伤口的可行治疗方法。我们之前的工作已经确定了 细胞因子和独特细胞类型的重要性，包括皮肤中的成纤维细胞亚型和巨噬细胞 小鼠伤口愈合。本转化研究提案的总体目标是定义 成纤维细胞亚型促进老年人和糖尿病患者伤口修复的分子机制 皮肤以及如何将其转化为慢性伤口的新型治疗方式。 我们的中心假设是成纤维细胞的异质性对于损伤后皮肤的适当修复是必不可少的 并且随着糖尿病和年龄的增长而改变。这一假设是基于我们的发现：1）多个 类成纤维细胞有助于损伤后的皮肤修复; 2）人皮肤伤口含有多种成纤维细胞， 3）伤口生长因子如Igf 1特异性地促进成纤维细胞的增殖， 在小鼠伤口和体外的非纤维化成纤维细胞群中， 糖尿病; 4）成纤维细胞的特定群体在老化的皮肤中丢失。根据这些初步数据， 我们在皮肤伤口愈合方面的发现记录，以及我们的整形外科和皮肤科专家团队 细胞/发育生物学，我们非常有能力执行所提出的实验。 我们计划客观地检验我们的中心假设，并通过以下方式实现这一提议的目标： 追求以下具体目标：1）确定成纤维细胞中IGF 1 R的缺乏是否改变了成纤维细胞中IGF 1 R的表达。 2）评估人真皮成纤维细胞的异质性和IGF-1反应 3）确定是否移植年轻的成纤维细胞和/或成纤维细胞亚群; IGF 1治疗可以改善老年和糖尿病小鼠皮肤的伤口愈合缺陷。 我们将使用体外细胞功能研究来检验这一假设，这些研究涉及来源于 人类患者以及啮齿动物模型中的体内研究。这项工作将大大提高我们的 了解皮肤伤口愈合过程中成纤维细胞的功能，以及年龄和 糖尿病预计这项翻译工作将确定协调皮肤的新因素 并为治疗慢性不愈合提供额外的治疗靶点 在我们的退伍军人的伤口。

Defining translational mechanisms to promote regenerative healing of chronic wounds Abstract: Chronic wounds are common among our veterans, often impacting negatively on their ability to achieve a high quality of life as productive members of our society, and the care of these wounds and their sequelae consumes a significant portion of resources within the Veterans Health Administration. The ultimate objective of the research described in this proposal is to develop solutions that allow durable and regenerative healing of these wounds. Patients who are aged and/or diabetic are at major risk for developing difficult non-healing wounds, and diabetes occurs among veterans at about three times the rate of the general US population. To effectively manage these wounds, it is essential to understand the normal healing process and engineer treatments that promote the physical and biochemical environment of healing tissue. Pathologically, our identification of specific subclasses of cells within human skin and how they control skin wound healing carries the potential to ameliorate skin infections and chronic wounds. Our long-term goal is to translate our understanding of the cellular and molecular interactions that drive skin repair into viable treatments for chronic wounds. Our prior work has identified the importance of cytokines and unique cell types including fibroblast subtypes and macrophages in skin wound healing in mice. The overall objective of this translational research proposal is to define the molecular mechanisms by which fibroblast subtypes contribute to wound repair in aged and diabetic skin and how that can be translated into novel treatment modalities for chronic wounds. Our central hypothesis is that fibroblast heterogeneity is essential for proper skin repair after injury and is altered with diabetes and age. This hypothesis is based on our findings that: 1) Multiple classes of fibroblasts contribute to skin repair after injury; 2) Human skin wounds contain multiple fibroblast populations; 3) Wound growth factors such as Igf1 specifically contribute to proliferation of non-fibrotic fibroblast populations in mouse wounds and in vitro and Igf1R expression is altered in diabetes; 4) Specific populations of fibroblasts are lost in aged skin. Based on these preliminary data, our record of discovery in skin wound healing, and our team of experts from plastic surgery and skin cell/developmental biology, we are exceptionally capable of executing the proposed experiments. We plan to objectively test our central hypothesis and obtain the objective of this proposal by pursuing the following specific aims: 1) Determine whether the lack of IGF1R in fibroblasts alters wound healing in mice; 2) Assess the heterogeneity and IGF-1 response of human dermal fibroblast subpopulations in wounds; and 3) Determine whether transplantation of young fibroblasts and/or IGF1 treatment can ameliorate wound healing defects in aged and diabetic mouse skin. We will test this hypothesis using in vitro cell functional studies involving fibroblasts derived from human patients as well as in vivo studies in a rodent model. This work will greatly increase our understanding of fibroblast function during skin wound healing and how that is impacted by age and diabetes. It is expected that this translational work will identify novel factors that coordinate skin wound healing and provide additional therapeutic targets for the treatment of chronic non-healing wounds in our veterans.