Functions of secreted Wnt inhibitors in hair follicle patterning and regenerative activity

分泌型 Wnt 抑制剂在毛囊模式形成和再生活性中的功能

• 批准号: 10625345
• 负责人: Alicia Ho
• 金额: $ 4.61万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625345
• 关键词: Acceleration; Adult; Affect; Alleles; Apoptosis; Biological Assay; Biological Models; Biology; Characteristics; Communication; Cre lox recombination system; Data; Dermal; Dermis; Development; Differentiation Antigens; Disease; Doctor of Philosophy; Dorsal; Doxycycline; Ear; Embryo; Embryonic Development; Environment; Exhibits; Fellowship; Female; Gene Deletion; Gene Expression; Genes; Genetic; Goals; Growth; Growth Disorders; Hair; Hair follicle structure; Heterogeneity; Heterozygote; Histology; Human; Immunofluorescence Immunologic; In Situ Hybridization; Knockout Mice; Life; Ligands; LoxP-flanked allele; Male Pattern Baldness; Mentorship; Miniaturization; Molecular; Morphogenesis; Mus; Pathway interactions; Pattern; Phase; Play; Process; Proliferating; Property; Regenerative capacity; Regenerative research; Research; Role; Scalp structure; Science; Signal Pathway; Signal Transduction; Skin; Skin Pigmentation; Techniques; Testing; Therapeutic; Thick; Thinness; Time; Training; Variant; Woman; Work; base; beta catenin; career; density; experience; experimental study; external ear auricle; hair regeneration; improved; inhibitor; men; mutant; new therapeutic target; novel therapeutic intervention; novel therapeutics; postnatal; psychologic; regenerative; regional difference; research and development; single-cell RNA sequencing; skin disorder; skin organogenesis; social; tongue papilla

PROJECT SUMMARY Different regions of skin exhibit distinct properties and functions, including their patterns of hair follicle distribution and regenerative properties. Hair loss diseases often have regional effects due to this variation in skin biology. An extremely common example in both men and women is androgenetic alopecia, or AGA, also known as male pattern baldness and female pattern hair loss. AGA affects only scalp hair, and is characterized by disruption of signaling in and around the hair follicle (HF) that leads to inhibition of the hair growth cycle and hair follicle miniaturization. Hair loss diseases can have negative psychological, social, and financial impacts. Current treatments are only partially effective, and the molecular basis for regional variation in skin and hair growth is not well-characterized. Delineating the mechanisms underlying skin and hair heterogeneity has the potential to identify improved therapeutic approaches to hair loss and skin diseases. Wnt/β-catenin signaling is crucial for the initiation, development, and regeneration of hair, and can be modulated by endogenous secreted Wnt inhibitors. Dkk2 and Sostdc1 are secreted Wnt inhibitors that have regionally distinct expression patterns, with relatively higher expression levels in regions of embryonic mouse skin that develop poorly regenerative hair follicles or remain completely hairless. Preliminary data show that Dkk2 and Sostdc1 are also upregulated in the dermal papilla of postnatal HFs as the anagen growth phase ends. The proposed research will test the global hypothesis that Dkk2 and Sostdc1 dictate whether skin will be hair-bearing, determine HF size and regenerative capacity, and control adult HF cycling. Aim 1 will delineate the roles of Dkk2 and Sostdc1 in HF patterning during embryogenesis using Dkk2/Sostdc1 global null mice. Aim 2 will determine the postnatal functions of these inhibitors in regulating HF size and cycling independent of their embryonic roles by inducing deletion postnatally in Dkk2/Sostdc1 floxed mice. Successful completion of the proposed aims has the potential to identify novel therapeutic targets for hair loss diseases and will provide the candidate with rigorous training in experimental techniques and science communication that is essential for an independent research career. Supplemented with the proposed mentorship experiences and collaborative intellectual environment, this fellowship will accelerate the career progress of a promising PhD Candidate who is strongly committed to skin development and regeneration research.

项目摘要 皮肤的不同区域表现出不同的特性和功能，包括它们的毛囊模式 分布和再生性能。脱发疾病往往有区域性影响，由于这种变化， 皮肤生物学男性和女性中一个非常常见的例子是雄激素性脱发，或阿加，也 男性型脱发和女性型脱发。阿加仅影响头皮毛发，其特征在于 通过破坏毛囊内和周围的信号传导（HF），导致毛发生长周期的抑制， 毛囊小型化脱发疾病可能会产生负面的心理，社会和经济影响。 目前的治疗方法只是部分有效，皮肤和毛发区域性变化的分子基础 增长没有得到很好的描述。描述皮肤和毛发异质性的潜在机制， 潜在的确定改善脱发和皮肤病的治疗方法。Wnt/β-catenin信号传导是 对于毛发的起始、发育和再生至关重要，并且可以通过内源性分泌来调节 Wnt抑制剂。Dkk 2和Sostdc 1是分泌的Wnt抑制剂，具有区域性不同的表达模式， 在胚胎小鼠皮肤再生能力差的区域表达水平相对较高 毛囊或保持完全无毛。初步数据显示，Dkk 2和Sostdc 1也被上调， 在生长期结束时，在出生后HFs的毛乳头中。拟议的研究将测试 Dkk 2和Sostdc 1决定皮肤是否有毛发，决定HF大小和 再生能力，并控制成人HF循环。目的1阐明Dkk 2和Sostdc 1在心力衰竭中的作用 使用Dkk 2/Sostdc 1全基因敲除小鼠在胚胎发生过程中形成图案。目标2将决定产后 这些抑制剂的功能，在调节HF大小和周期独立的胚胎作用，通过诱导 在Dkk 2/Sostdc 1 floxed小鼠中出生后缺失。成功实现拟议目标， 潜在的确定脱发疾病的新的治疗目标，并将提供严格的候选人 实验技术和科学交流的培训是独立研究所必需的 事业辅以拟议的导师经验和协作性知识环境， 该奖学金将加速有前途的博士候选人的职业发展，他们坚定地致力于 皮肤发育和再生研究。