Investigating the role of JAK/STAT3 signaling in the hair cycle

研究 JAK/STAT3 信号在毛发周期中的作用

• 批准号: 10249963
• 负责人: Yoo Jin Lee
• 金额: $ 3.42万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249963
• 关键词: Ablation; Alopecia; Autoimmune Diseases; Biology; Cell Proliferation; Chemotherapy-Oncologic Procedure; Clinical; Complex; Data; Defect; Dermal; Disease; Distress; Environment; Epidermis; Gene Expression Profiling; Genetic; Goals; Growth; Growth Factor; Hair; Hair follicle structure; Health; Homeostasis; Hormones; Human; Immunoblotting; Immunofluorescence Immunologic; Injections; Investigation; JAK2 gene; Janus kinase; Knock-out; Knockout Mice; Leptin; Literature; Male Pattern Baldness; Mediating; Metabolism; Modeling; Molecular; Mus; Natural regeneration; Nature; Obesity; Organ; Pathogenesis; Pathway interactions; Patients; Pattern; Pharmacology; Phase; Phenocopy; Phenotype; Play; Process; Regulation; Role; STAT protein; STAT3 gene; Signal Pathway; Signal Transduction; Skin; Source; Stat5 protein; TREM2 gene; Therapeutic; Time; Trichotillomania; Wild Type Mouse; Work; body system; cytokine; genetic manipulation; inhibitor/antagonist; insight; leptin receptor; macrophage; migration; mouse model; new therapeutic target; novel; oncostatin M; peptide hormone; psychological distress; receptor; small molecule; stem cells

PROJECT SUMMARY The hair follicle is a complex mini-organ that undergoes continuous cycles of regression (catagen), quiescence (telogen), growth (anagen), and shedding (exogen) in a process known as the hair cycle. A number of hair loss disorders including androgenetic alopecia, the most common form of hair loss in humans, are thought to be due to defects in hair cycle progression. The therapeutic options for such hair loss disorders nonetheless remain limited, owing to an incomplete understanding of the molecular mechanisms that govern hair cycling. Recent evidence from our lab and others uncovered a role for JAK/STAT signaling in the control of hair cycling. Specifically, we demonstrated that JAK/STAT5 signaling downstream of Oncostatin M produced by Trem2+ dermal macrophages maintains hair follicle quiescence during telogen. Meanwhile, previous studies have shown that JAK/STAT3 signaling may play the opposite role in hair cycling, since STAT3 epidermal knockout mice remain arrested in telogen; however, the mechanism by which JAK/STAT3 governs the hair cycle, including its upstream activating factor(s), remain unknown. In this study, we will investigate the molecular mechanisms of JAK/STAT3-driven control of the hair cycle, with a focus on the telogen-to-anagen transition. In Aim 1, we will define the temporal and spatial pattern of JAK/STAT3 signaling in the hair follicle and the surrounding dermal environment throughout the hair cycle. In Aim 2, we will interrogate the functional role of JAK/STAT3 in hair cycling by both pharmacologically and genetically perturbing JAK/STAT3 signaling at specific points in the hair cycle. To achieve this, we will use a number of small-molecule JAK and STAT3 inhibitors, as well as inducible Cre-driven knockout mice that ablate STAT3 in specific skin and hair follicle compartments. In Aim 3, we will investigate the role of leptin, a 16 kDa hormone peptide that has been extensively studied in the context of obesity and metabolism, as a potential upstream activating factor of JAK/STAT3 signaling in hair cycling. Canonical leptin signaling is known to activate the JAK2/STAT3 axis, and previous studies as well as our Preliminary Data demonstrate that leptin signaling is required for the telogen-to-anagen transition, thereby inviting further investigation of leptin as a candidate upstream factor of JAK/STAT3 in anagen induction. Neither JAK/STAT3 nor leptin have been extensively studied in hair biology relative to other signaling pathways and hormones, therefore, these studies will greatly expand our current understanding of skin and hair follicle homeostasis. Furthermore, we anticipate that our findings can be extrapolated to provide novel insight into the pathogenesis of hair loss disorders, and thereby identify novel therapeutic targets for different types of alopecia.

项目摘要 毛囊是一个复杂的微型器官，经历了连续的退化周期（退化期），静止期， 毛发生长周期包括毛发生长终期（休止期）、生长期（生长期）和脱落期（外生期）。脱发的原因 包括雄激素性脱发（人类最常见的脱发形式）在内的疾病被认为是由于 毛发周期进展中的缺陷。尽管如此，这种脱发疾病的治疗选择仍然存在 有限的，由于不完全理解的分子机制，支配头发周期。最近 来自我们实验室和其他实验室的证据揭示了JAK/STAT信号在毛发周期控制中的作用。 具体地，我们证明了由Trem 2+产生的抑瘤素M下游的JAK/STAT 5信号传导 真皮巨噬细胞在休止期维持毛囊静止。同时，之前的研究表明， JAK/STAT 3信号传导可能在毛发周期中发挥相反的作用，因为STAT 3表皮敲除小鼠 然而，JAK/STAT 3调控毛发周期的机制，包括其 上游激活因子，仍然未知。在这项研究中，我们将探讨的分子机制， JAK/STAT 3驱动的毛发周期控制，重点是休止期到生长期的过渡。在目标1中，我们 确定毛囊和周围真皮中JAK/STAT 3信号传导的时间和空间模式 在整个头发周期中。在目的2中，我们将询问JAK/STAT 3在头发中的功能作用。 在头发中的特定点通过基因和遗传干扰JAK/STAT 3信号传导进行循环 周期为了实现这一点，我们将使用一些小分子JAK和STAT 3抑制剂，以及诱导性的 Cre-driven敲除小鼠，消融特定皮肤和毛囊隔室中的STAT 3。在目标3中，我们 研究瘦素的作用，瘦素是一种16 kDa的激素肽，已被广泛研究， 肥胖和代谢，作为头发周期中JAK/STAT 3信号传导的潜在上游激活因子。 已知典型的瘦素信号传导激活JAK 2/STAT 3轴，先前的研究以及我们的研究表明， 初步数据表明，瘦素信号传导是需要的休止期到生长期的过渡，从而 这促使进一步研究瘦素作为JAK/STAT 3的候选上游因子在生长期诱导中的作用。既不 JAK/STAT 3和瘦素在毛发生物学中相对于其他信号传导途径进行了广泛研究， 因此，这些研究将大大扩展我们目前对皮肤和毛囊的理解， 体内平衡此外，我们预计，我们的研究结果可以外推，以提供新的见解， 本发明的目的是研究脱发病症的发病机制，从而鉴定不同类型脱发的新治疗靶标。