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.

项目总结 皮肤的不同区域表现出不同的属性和功能，包括它们的毛囊模式 分布和再生特性。脱发疾病通常具有地区性影响，这是由于 皮肤生物学。在男性和女性中，一个非常常见的例子是雄激素性脱发，或AGA，也 被称为男性型秃顶和女性型脱发。AGA只影响头皮毛发，其特征是 通过干扰毛囊(HF)内和周围的信号导致抑制毛发生长周期和 毛囊小型化。脱发疾病可能会对心理、社会和经济产生负面影响。 目前的治疗只有部分有效，皮肤和头发区域性变异的分子基础 增长并没有得到很好的描述。描述皮肤和头发异质性的潜在机制有 有可能确定改进的脱发和皮肤病治疗方法。WNT/β-连环蛋白信号转导系统 对毛发的启动、发育和再生至关重要，并可受内源性分泌的调节 WNT抑制剂。Dkk2和Sostdc1是分泌的具有区域不同表达模式的Wnt抑制物， 在胚胎小鼠皮肤再生不良的区域有相对较高的表达水平 毛囊或保持完全无毛。初步数据显示，Dkk2和Sostdc1也上调 在出生后HFs的毛乳头中，随着生长期的结束。这项拟议的研究将测试 全球假设，Dkk2和Sostdc1决定皮肤是否会有毛发，决定HF大小和 再生能力，控制成人高频骑行。目标1将描述Dkk2和Sostdc1在心衰中的作用 使用Dkk2/Sostdc1全局缺失小鼠进行胚胎发育过程中的图案形成。目标2将决定出生后 这些抑制物在调节HF大小和周期中的作用不依赖于它们的胚胎作用 Dkk2/Sostdc1系小鼠出生后缺失。成功完成拟议的目标将使 有可能发现脱发疾病的新治疗靶点，并将为候选人提供严格的 对独立研究至关重要的实验技术和科学交流方面的培训 职业生涯。辅以拟议的导师经验和协作智力环境， 这一奖学金将加速一位有前途的博士生的职业发展，他坚定地致力于 皮肤发育和再生研究。