Regulation of Quiescence and Activation in Skin Stem Cells

描述（由申请人提供）：本提案的长期目标是了解干细胞的活性如何被适当调节以维持体内平衡和组织完整性。毛囊，重要的皮肤附属物之一，是解决这个问题的理想范例。毛囊经历生长期（生长期）、破坏期（衰退期）和休止期（休止期）的周期。毛囊干细胞（HFSCs）位于毛囊的一个永久性突起，这个结构被称为凸起。HFSCs很少处于膨胀周期。在正常的体内平衡中，HFSCs只在一个非常短暂的生长期窗口中增殖，而在所有其他阶段保持静止。HFSCs在受伤时也会被激活。HFSC活性的失调会导致严重的后果。例如，脱发（脱发）和伤口愈合延迟可能是由HFSCs激活效率低下引起的。相反，皮肤肿瘤，如基底细胞癌和鳞状细胞癌，可源于HFSC的过度增殖。干细胞的活性在很大程度上受其微环境的影响，即生态位。传统上，关于生态位的研究只关注周围的异源细胞类型，即来自不同谱系的细胞。包括我自己在内的最近研究发现，干细胞后代在几种脊椎动物和无脊椎动物干细胞系统中作为生态位成分的重要性，这是以前未被认识到的。在毛囊中，我的初步研究已经确定了两个重要的后代种群是至关重要的

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand how the activity of stem cells is properly regulated to maintain homeostasis and tissue integrity. The hair follicle, one of the important skin appendages, is an ideal paradigm to address this problem. Hair follicles undergo cycles of growth (anagen), destruction (catagen) and rest (telogen) phases. Hair follicle stem cells (HFSCs) are located in a permanent protrusion of the hair follicle, a structure known as the bulge. HFSCs in the bulge cycle infrequently. During normal homeostasis, HFSCs only proliferate in a very transient window of anagen, while remaining quiescent during all the other phases. HFSCs can also become activated upon wounding. Dis-regulation of HFSC activity results in severe consequences. For example, alopecia (hair loss) and delayed wound healing may arise from inefficient activation of HFSCs. On the contrary, skin tumors, such as basal cell carcinoma and squamous cell carcinoma, can derive from HFSC hyper-proliferation. Stem cell activity is heavily influenced by their microenvironment, known as the niche. Traditionally, studies about niche focus only on the surrounding heterologous cell types, i.e., cells originated from a different lineage. Recent studies including my own discover the importance of stem cell progeny as niche components in several vertebrate and invertebrate stem cell systems, which is previously unrecognized. In the hair follicle, my preliminary studies have identified two important progeny populations as critical regulators for HFSC proliferation. The central hypothesis to be tested by this proposal is that feedback regulation from HFSC progeny is crucial for the proper behavior and activity of HFSCs. This hypothesis will be tested in this grant application by experiments that: 1) examine candidate signals expressed by the progeny 2) determine the contributions of the progeny to HFSC activation under physiological and pathological conditions and 3) identify novel functional factors expressed by the progeny to regulate HFSCs. Candidate signals will be investigated during the mentored phase. The contributions of progeny under dynamic conditions as well as identified novel factors expressed by the progeny will be follow-up during the independent phase. Successful completion of the proposed experiments will significantly advance our understanding of the cell types and signals that regulate HFSC proliferation and quiescence. In addition, these proposed studies will potentially lead to the development of therapeutic treatments for skin disorders associate with aberrant stem cell activity. My long-term career goal is to lead a successful, independent, and well-funded laboratory studying skin and stem cell biology. My graduate and postdoctoral training up to date has prepared me technically and intellectually to develop rigorous research projects. This career development award and my proposed research plan will further provide me with opportunities to expand my knowledge in skin stem cell biology and mouse genetics, gain new skills in bioinformatics analysis, mouse embryo manipulation, image-based FACS analysis, and further accumulate experience to improve mentoring, presentation, and writing skills, all of which are critical to my fuure success as an independent researcher. The reagents generated during the mentored phase will also help to build up my research program in the independent phase. The Rockefeller University together with its two neighboring institutions, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, offer a prime research environment and many workshops and courses to support my proposed research and my career development. I will have constant interactions with my mentor Dr. Elaine Fuchs, my collaborator Dr. Olivier Elemento, and the skin and mouse developmental biology communities in the New York area. Together they will assess my progress and provide critique or advice. In summary, the proposed studies and career development plan will better prepare me for my independent scientific career, ensure that I achieve my long-term career goals, and allow me to make continuous contributions towards our understanding of how stem cell activity is regulated in homeostasis and disease.