Live Imaging of Skin Regeneration

描述(申请人提供)：组织动态平衡和再生由干细胞维持，干细胞既能补充自己的祖细胞库，又能在组织的整个生命周期中产生分化细胞。干细胞所处的环境，即所谓的利基环境，调节着它们的特殊能力。干细胞调节是组织功能的关键。干细胞不能适当激活会阻碍组织修复并导致组织衰竭，而干细胞激活不当会导致过度生长和癌症。因此，在研究干细胞及其利基环境中阐明的基础知识在迈向治疗一系列疾病的道路上可能是无价的。我们仍然缺乏关于干细胞调节的动态机制的关键知识。获取这种知识的主要障碍之一是无法进入一个明确界定的利基市场，在这个利基市场中，可以观察和操纵再生的离散步骤。我实验室研究的目标是了解控制干细胞的细胞和信号机制，以及疾病状态下的错误。为了理解干细胞生物学的这些基本原理，我们利用皮肤毛囊中独特的哺乳动物干细胞生态位，因为它具有特殊的可及性和明确的结构。我的实验室已经建立了一种活体策略，以可视化毛囊干细胞利基的成分，以便操纵它们，并具体询问当被干扰时，哪些信号会导致疾病。使用一种新的、非侵入性的双光子成像方法，我们在活体小鼠身上实时跟踪毛囊干细胞的生态位。通过这些手段，我们研究了上皮干细胞及其后代在生理性毛发再生过程中的行为，以及间充质生态位如何影响他们的行为。这项提议的目标是使用尖端成像技术、基因操作和细胞生物学的综合方法来促进我们对激活干细胞和维持组织再生的机制的理解。这些实验将是实时揭示体内干细胞利基成分动态的关键。鉴于利基成分和信号已被证明在其他器官中是保守的，我们关于管理干细胞的基本原理的发现可能会与其他组织相关，并将推进治愈疾病的治疗策略。

DESCRIPTION (provided by applicant): Tissue homeostasis and regeneration are sustained by stem cells, which are cells able to both replenish their own progenitor cell pool as well as give rise to differentiated cells throughout the life of a tissue. The environment in which stem cells reside, the so-called niche, regulate their special abilities. Stem cell regulation is key fo tissue function. Failure to properly activate stem cells will hinder tissue repair and lead to orga failure, while improper stem cell activation will lead to overgrowth and cancer. Therefore, the basic elucidated in researching stem cells and their niches may be invaluable in moving towards cures for a range of diseases. We still lack critical knowledge of the dynamic mechanisms of stem cell regulation. One of the major obstacles to gaining that knowledge is lack of access to a well-defined niche in which the discrete steps of regeneration can be observed and manipulated. The goal of my laboratory research is to understand the cellular and signaling mechanisms that govern stem cells and what goes awry in a disease state. To understand these fundamental principles of stem cell biology, we make use of the unique mammalian stem cell niche within the skin hair follicle because of its exceptional accessibility and well-defined structure. My laboratory has established an in vivo strategy to visualize the components of the hair follicle stem cell niche, in order to manipulate them and to ask specifically which signals, when disrupted, give rise to disease. Using a novel, non-invasive, two-photon imaging approach we follow the stem cell niche of the hair follicle in real-time in live mice. By these means, we have studied the behavior of the epithelial stem cells and their progeny during physiological hair regeneration and how the mesenchymal niche influences their behavior. The goal of this proposal is to use an integrated approach of cutting edge imaging technology, genetic manipulation and cell biology to advance our understanding of the mechanisms that activate stem cells and sustain tissue regeneration. These experiments will be key to reveal the dynamics of stem cell niche components in vivo in real time. Given that niche components and signaling have been shown to be conserved in other organs, our findings about the fundamental principles that govern stem cells will likely be relevant to other tissues, and will advance therapeutic strategies for the cure of diseases.