Live Imaging of Skin Regeneration

描述（由申请人提供）：组织稳态和再生由干细胞维持，干细胞是能够补充其自身祖细胞库以及在组织的整个生命周期中产生分化细胞的细胞。干细胞所处的环境，即所谓的生态位，调节着它们的特殊能力。干细胞调节是组织功能的关键。不能正确激活干细胞将阻碍组织修复并导致器官衰竭，而不当的干细胞激活将导致过度生长和癌症。因此，在研究干细胞及其生态位中阐明的基本原理可能对治疗一系列疾病非常宝贵。 我们仍然缺乏对干细胞调控的动态机制的关键知识。获得这种知识的主要障碍之一是缺乏一个明确界定的利基，在这个利基中，可以观察和操纵再生的离散步骤。我的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，我们利用皮肤毛囊内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体内策略来可视化毛囊干细胞生态位的组成部分，以便操纵它们并具体询问哪些信号，当被破坏时，会引起疾病。使用一种新的，非侵入性的，双光子成像方法，我们在活体小鼠中实时跟踪毛囊的干细胞龛。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它们的行为。该提案的目标是使用尖端成像技术，遗传操作和细胞生物学的综合方法，以促进我们对激活干细胞和维持组织再生机制的理解。这些实验将是揭示干细胞龛成分在体内真实的时间动态的关键。鉴于生态位成分和信号传导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则的发现可能与其他组织相关，并将推进疾病治疗的治疗策略。

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.