Regulation of Quiescence and Activation in Skin Stem Cells

皮肤干细胞静止和激活的调节

• 批准号: 8509979
• 负责人: Ya-Chieh Hsu
• 金额: $ 9.65万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509979
• 关键词: Address; Alopecia; Animals; Applications Grants; Area; Basal cell carcinoma; Behavior; Bioinformatics; Biology; Cell Lineage; Cell Proliferation; Cells; Communities; Critiques; Data; Development Plans; Developmental Biology; Disease; Educational workshop; Embryo; Ensure; Environment; Equilibrium; Erinaceidae; Feedback; Funding; Future; Genetic; Genomics; Goals; Growth; Hair; Hair follicle structure; Homeostasis; Image; Impaired wound healing; Institution; Invertebrates; K-Series Research Career Programs; Keratin; Knock-out; Knowledge; Laboratory Study; Lead; Learning; Life; Mediating; Memorial Sloan-Kettering Cancer Center; Mentors; Mitogens; Mus; Natural regeneration; New York; Organ; Papilloma; Phase; Physiological; Play; Population; Proliferating; Reagent; Regenerative Medicine; Regulation; Research; Research Personnel; Research Project Grants; Rest; Role; Signal Transduction; Skin; Skin Cancer; Skin Neoplasms; Source; Squamous cell carcinoma; Stem cells; Structure; System; Tamoxifen; Testing; Tissues; Universities; WNT Signaling Pathway; Wound Healing; Writing; adult stem cell; appendage; base; career; career development; cell behavior; cell type; clinical application; design; experience; follow-up; improved; in vivo; injury and repair; insight; lentiviral-mediated; medical schools; novel; post-doctoral training; prevent; programs; public health relevance; research study; response; self-renewal; skills; skin disorder; smoothened signaling pathway; stem cell biology; stem cell niche; success; therapeutic development; tumor

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.

描述（由申请人提供）：该提案的长期目标是了解如何正确调节干细胞的活性以维持体内平衡和组织完整性。毛囊作为重要的皮肤附属器之一，是解决这一问题的理想范例。毛囊经历生长（毛发生长初期）、破坏（毛发生长中期）和静止（毛发生长终期）阶段的周期。毛囊干细胞 (HFSC) 位于毛囊的永久突出物中，这种结构称为凸起。 HFSC 很少处于膨胀周期。在正常稳态期间，HFSC 仅在生长期的一个非常短暂的窗口中增殖，而在所有其他阶段保持静止。 HFSC 也可以在受伤时被激活。 HFSC 活动的失调会导致严重后果。 例如，脱发（脱发）和伤口愈合延迟可能是由于 HFSC 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，可能源自 HFSC 过度增殖。干细胞的活性很大程度上受到其微环境（称为生态位）的影响。传统上，关于生态位的研究仅关注周围的异源细胞类型，即来自不同谱系的细胞。最近的研究，包括我自己的研究，发现干细胞后代作为几种脊椎动物和无脊椎动物干细胞系统中的生态位成分的重要性，这是以前未被认识到的。在毛囊中，我的初步研究已确定两个重要的后代群体至关重要 HFSC 增殖的调节因子。该提案要测试的中心假设是 HFSC 后代的反馈调节对于 HFSC 的正常行为和活动至关重要。该假设将在本拨款申请中通过实验进行测试：1）检查后代表达的候选信号2）确定后代在生理和病理条件下对HFSC激活的贡献以及3）识别后代表达的新功能因子监管 HFSC。候选信号将在指导阶段进行调查。后代在动态条件下的贡献以及后代表达的已识别的新因素将在独立阶段进行跟踪。成功完成所提出的实验将显着增进我们对调节 HFSC 增殖和静止的细胞类型和信号的理解。此外，这些拟议的研究将有可能导致与异常干细胞活性相关的皮肤疾病的治疗方法的开发。我的长期职业目标是领导一个成功、独立且资金充足的实验室，研究皮肤和干细胞生物学。 迄今为止，我的研究生和博士后培训使我在技术和智力上为开发严谨的研究项目做好了准备。这个职业发展奖和我提出的研究计划将进一步为我提供机会扩展我在皮肤干细胞生物学和小鼠遗传学方面的知识，获得生物信息学分析、小鼠胚胎操作、基于图像的FACS分析方面的新技能，并进一步积累经验提高指导、演讲和写作技巧，所有这些对于我作为一名独立研究员未来的成功至关重要。 在指导阶段产生的试剂也将有助于在独立阶段建立我的研究计划。洛克菲勒大学及其两个邻近的机构——纪念斯隆-凯特琳癌症中心和威尔康奈尔医学院——提供了一流的研究环境和许多研讨会和课程，以支持我提出的研究和职业发展。我将与我的导师 Elaine Fuchs 博士、我的合作者 Olivier Elemento 博士以及纽约地区的皮肤和小鼠发育生物学界保持持续的互动。他们将一起评估我的进步并提供批评或建议。总之，拟议的研究和职业发展计划将使我更好地为我的独立科学生涯做好准备，确保我实现我的长期职业目标，并使我能够为我们对干细胞活性如何在稳态中调节的理解做出持续的贡献和疾病。