Understanding Skin Tissue Repair in Live Mammals

了解活体哺乳动物的皮肤组织修复

• 批准号: 10091970
• 负责人: Valentina Greco
• 金额: $ 55.78万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091970
• 关键词: Address; Affect; Behavior; Biology; Cancer Patient; Cell Communication; Cell Proliferation; Cells; Cellular biology; Cessation of life; Chronic; Complex; Diabetes Mellitus; Disease; Environment; Epidermis; Epithelial; Epithelial Cells; Failure; Foundations; Future; Generations; Genetic; Goals; Hair follicle structure; Health; Health Care Costs; Healthcare Systems; Homeostasis; Hour; Human; Image; Imaging technology; Immune; Individual; Inflammation; Injury; Knowledge; Label; Laboratories; Langerhans cell; Location; Malignant Neoplasms; Mammals; Methods; Mus; Natural regeneration; Nature; Obesity; Organ; Patients; Pharmacology; Population; Positioning Attribute; Process; Proliferating; Public Health; Regulation; Research; Role; Science; Signal Transduction; Site; Skin; Skin Tissue; Skin injury; Skin repair; T-Lymphocyte; Techniques; Therapeutic; Time; Tissues; Transforming Growth Factor beta; Transgenic Mice; aging population; behavioral outcome; beta catenin; cell behavior; cell motility; cell type; chronic wound; cost; diabetic patient; diabetic ulcer; epithelial stem cell; experimental study; genetic manipulation; imaging approach; improved; in vivo; injury and repair; innovation; insight; intravital imaging; intravital microscopy; migration; mouse model; novel; novel strategies; novel therapeutics; repaired; response; spatiotemporal; stem cell function; stem cell population; stem cells; tissue regeneration; tissue repair; two-photon; wound; wound closure; wound healing

SUMMARY Skin protects our body against the outer environment, and its ability to repair upon injury is directly connected to both disease and survival. Failure to properly repair injured tissue can result in severe damage, such as the formation of chronic wounds, which are associated with severe complications and even death. Approximately 6.5 million people in the US suffer from chronic non-healing skin wounds, such as diabetic ulcers. At least US$25 billion is spent annually to treat chronic wounds, and this cost is skyrocketing due to increasing health care costs, an aging population and the growing rates of diabetes, cancer and obesity. Thus, chronic wounds represent a substantial burden on public health and the health care system. We still lack fundamental knowledge of distinct cellular behaviors that are coordinated to achieve tissue regeneration and repair. The goal of this proposal is to unravel how cell behaviors are properly orchestrated on the single-cell and tissue-scale level during repair. The critical barrier to addressing these fundamental questions lies in the inability to study these dynamic processes in an intact mammal. Further, interrogating skin repair is complicated by the coexistence epithelial stem cells intermixed with resident immune cells, both of which are implicated in the repair process. To this end, my laboratory has established an in vivo strategy to directly visualize and manipulate epithelial cells and immune cells in the skin epithelium of live mice, taking advantage of its unique accessibility, continuous regeneration throughout its lifetime, and efficient repair. We utilize a novel, non-invasive two-photon imaging approach to follow epithelial and immune cells during the repair process. We combine intravital microscopy with methods that we developed to manipulate distinct epithelial cell repair behaviors or resident cell types in vivo. This integrated approach allows us to dissect the coordination and functional significance of distinct cell activities, populations and interactions during repair. Thus, we have begun to understand the complex interplay between distinct epithelial cell behaviors, and between distinct cell types within the epidermis, that contribute to wound closure. The goal of this proposal is to advance our understanding of how cell populations and behaviors are orchestrated to achieve wound repair in skin, by using an integrated approach of cutting edge imaging technology, genetic manipulation and cell biology. Given that many aspects of wound repair are widely conserved in other organs, our findings will be relevant to other tissues as well, and will provide an important foundation to improve wound repair in a variety of patients.

总结 皮肤保护我们的身体免受外部环境的影响，它在受伤后的修复能力直接影响我们的身体。 与疾病和生存息息相关。不能正确修复受伤的组织可能导致严重的损伤， 例如慢性伤口的形成，这与严重的并发症甚至死亡有关。 在美国大约有650万人患有慢性非愈合性皮肤伤口，例如糖尿病性皮肤伤口。 溃疡至少 每年花费250亿美元用于治疗慢性伤口，由于 不断增加的医疗保健费用、人口老龄化以及糖尿病、癌症和肥胖症的发病率不断上升。因此，在本发明中， 慢性伤口对公共卫生和卫生保健系统造成了巨大的负担。 我们仍然缺乏对不同细胞行为的基本知识，这些细胞行为是协调的， 再生和修复。这项提议的目标是揭示细胞行为是如何在细胞内正确地协调的。 修复过程中的单细胞和组织尺度水平。解决这些基本问题的关键障碍 问题在于无法在完整的哺乳动物中研究这些动态过程。此外，询问皮肤 修复是复杂的共存上皮干细胞混合与居民免疫细胞， 这与修复过程有关。为此，我的实验室建立了一种体内策略， 直接可视化和操纵活小鼠皮肤上皮中的上皮细胞和免疫细胞，采取 其独特的可访问性，在其整个生命周期中持续再生和高效修复的优势。 我们利用一种新的非侵入性双光子成像方法来跟踪上皮细胞和免疫细胞 在修复过程中。我们将联合收割机活体显微镜与我们开发的 不同的上皮细胞修复行为或体内驻留细胞类型。这种综合方法使我们能够 解剖不同细胞活动，种群和相互作用的协调和功能意义， 修复.因此，我们已经开始了解不同上皮细胞行为之间的复杂相互作用， 表皮内不同细胞类型之间的差异，有助于伤口闭合。 这项提案的目的是促进我们对细胞群体和行为是如何 通过使用尖端成像的集成方法， 技术、基因操作和细胞生物学。鉴于伤口修复的许多方面广泛存在， 我们的发现也将与其他组织相关，并将提供重要的 为改善各种患者的伤口修复奠定基础。