Understanding Skin Tissue Repair in Live Mammals

了解活体哺乳动物的皮肤组织修复

基本信息

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
项目类别：
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

项目摘要

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.

概括皮肤保护我们的身体免受外界环境的影响，其受伤后的修复能力直接关系到身体的健康。与疾病和生存有关。未能正确修复受伤的组织可能会导致严重的损害，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 万人患有慢性不愈合的皮肤伤口，例如糖尿病溃疡。至少每年花费 250 亿美元用于治疗慢性伤口，并且由于以下原因，这一费用正在飙升：医疗保健费用不断增加、人口老龄化以及糖尿病、癌症和肥胖症发病率不断上升。因此，慢性伤口给公共卫生和卫生保健系统带来沉重负担。我们仍然缺乏对不同细胞行为的基本了解，这些行为是通过协调来实现组织的再生和修复。该提案的目标是揭示细胞行为是如何正确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研究完整哺乳动物的这些动态过程。此外，询问皮肤上皮干细胞与常驻免疫细胞混合共存，使得修复变得复杂。与修复过程有关。为此，我的实验室制定了体内策略直接可视化和操作活体小鼠皮肤上皮中的上皮细胞和免疫细胞，其独特的可访问性、在其整个生命周期内持续再生以及高效修复的优势。我们利用一种新颖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。我们将活体显微镜与我们开发的操纵方法相结合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剖析不同细胞活动、群体和相互作用的协调和功能意义维修。因此，我们已经开始了解不同上皮细胞行为之间复杂的相互作用，并且表皮内不同细胞类型之间的差异，有助于伤口闭合。该提案的目标是增进我们对细胞群体和行为如何发生的理解通过使用尖端成像的综合方法精心策划以实现皮肤伤口修复技术、基因操作和细胞生物学。鉴于伤口修复的许多方面已得到广泛应用由于在其他器官中保守，我们的发现也将与其他组织相关，并将提供重要的信息为改善各种患者的伤口修复奠定基础。