Extrinsic Regulation of Epidermal Homeostatasis

描述(由申请人提供)： 该项目的长期目标是更好地了解控制上皮干细胞活动和行为的组织微环境。上皮干细胞负责维持和再生自我更新的组织，如表皮、毛囊和乳腺。我们已经开始分析真皮下脂肪细胞在皮肤组织动态平衡中的生物学和功能。在哺乳动物中，白色脂肪组织通过脂肪堆积来储存能量，并可以作为旁分泌信号组织。在皮肤中，真皮下脂肪细胞构成了一个独特的脂肪组织储存库，它位于真皮成纤维细胞的下面，并在毛发生长过程中包围毛囊。数据表明，脂肪细胞可能调节毛囊周期和损伤，但真皮下脂肪细胞在皮肤中的作用尚不清楚。我们的初步数据显示，真皮下脂肪细胞对于毛囊循环和伤口愈合是必不可少的，并在皮肤中产生动态的微环境。我们推测，皮肤细胞和皮下脂肪细胞之间的相互作用对调节表皮的动态平衡至关重要。为了解决这一假设，我们将：1.通过A.分析遗传或药物诱导的脂肪生成缺陷导致真皮下脂肪细胞缺陷的小鼠，以及B.定义毛发周期中的脂肪生成，来表征真皮下脂肪细胞对于维持毛囊干细胞表型是否重要。2.通过确定真皮下脂肪细胞缺陷小鼠的伤口愈合反应和确定在伤口愈合过程中导致脂肪细胞再生的细胞机制，确定真皮下脂肪细胞是否在表皮伤口愈合中发挥作用。3.通过脂肪细胞的体外检测，确定皮下脂肪细胞调节皮肤动态平衡的分子机制，以探讨这些脂肪细胞在皮肤中信号分子表达的作用。脱发、毛干紊乱或慢性伤口的患者可能会从这项研究中受益。

DESCRIPTION (provided by applicant): The long-term goal of this project is to better understand the tissue microenvironment that controls the activity and behavior of epithelial stem cells. Epithelial stem cells are responsible for the maintenance and regeneration of self-renewing tissues such as epidermis, hair follicle, and mammary gland. We have begun analyzing the biology and function of subdermal adipocytes during skin tissue homeostasis. In mammals, depots of white adipose tissue store energy through lipid accumulation and can serve as paracrine signaling tissues. In the skin, subdermal adipocytes compose a unique adipose tissue depot that underlies the dermal fibroblasts and surrounds the hair follicle during hair growth. Data suggests that adipocytes may regulate hair follicle cycling and wounding, but the role of subdermal adipocytes in the skin is not known. Our preliminary data shows that subdermal adipocytes are essential for hair follicle cycling and wound healing and generate a dynamic microenvironment in the skin. We hypothesize that the interplay between skin cells and subdermal adipocytes is crucial for the regulation of epidermal homeostasis. To address this hypothesis, we will: 1. characterize whether subdermal adipocytes are important for maintaining the hair follicle stem cell phenotype by a. analyzing mice with genetic or pharmacologically induced defects in adipogenesis, resulting in defects in subdermal adipocytes and b. defining adipogenesis during the hair cycle. 2. determine if subdermal adipocytes play a role in epidermal wound healing by a. defining the wound healing response in mice with defects in subdermal adipocytes and b. defining the cellular mechanisms that lead to adipocyte regeneration during wound healing. 3. Define the molecular mechanisms by which subdermal adipocytes regulate skin homeostasis using in vitro assays with adipocytes to address the role of signaling molecule expression by these adipocytes in the skin. Patients with alopecia, hair shaft disorders, or chronic wounds could potentially benefit from this research.