A ROLE FOR NOGGIN AND BMP2/4 IN HAIR GROWTH CONTROL

NOGGIN 和 BMP2/4 在头发生长控制中的作用

• 批准号: 6256365
• 负责人: VLADIMIR A BOTCHKAREV
• 金额: $ 8.15万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6256365
• 关键词: alopecia; apoptosis; biological signal transduction; bone morphogenetic proteins; clinical research; embryogenesis; gene expression; gene targeting; genetically modified animals; growth factor receptors; hair follicle disorder; human subject; inhibitor /antagonist; laboratory mouse; receptor expression

Background: Despite different pathogenic mechanisms, two of the most common hair growth disorder (androgenic alopecia and alopecia areata) are characterized by hair follicle miniaturization with significant elongation of the resting stage, shortening of the growth stage of the hair cycle, and hair loss. Molecular signals that trigger hair follicle induction in embroyonic skin, as well as cyclic transformation from resting to active growth and from active growth to regression during postnatal development, in normal skin and in skin affected by hair growth disorders, are still poorly understood. Bone morphogenic proteins 2/4 (BMP2/4), members of transforming growth factor- beta/BMP superfamily, and their specific antagonist noggin, which binds BMP2/4 with high affinity and prevents their interactions with BMP receptors, play essential roles in the control of induction of ectodermal derivatives (neural tube, tooth, feather) and in the regulation of apoptotic cell death during development. While BMP2/4 inhibit morphogenesis and reduct the size of developing organs, the BMP- antagonist noggin stimulates morphogenesis and downregulates BMP- mediated apoptosis. Hypothesis: neutralization of BMP2/4 signaling by their antagonist noggin plays important roles: i) in the control of hair follicle induction during embryogenesis, ii) in the initiation of new hair growth phase in postnatal skin, iii) in the regulation of apoptosis-driven hair follicle regression in normal skin affected by most common hair growth disorders. Purpose: 1) Study hair follicle development in the embryonic skin of noggin knockout mice transplanted into SCID mice. 2) Characterize expression of noggin, BMP2/4, BMP-receptors during hair follicle cycling in normal postnatal C57BL/6 mouse and human skin, in the alopecia areata-affected C3H/HeJ mice, and in human skin affected by hair growth disorders. 3) Define effects of noggin/BMP2/4 on hair cycle in mouse and human skin in vivo and in situ. 4) Determine in vivo function of noggin in skin by generation of noggin-overexpressing mice under control of K14 and versican promoters. Significance: Investigation of the in vivo functions of noggin and BMP2/4 as putative modulators of hair follicle induction and cycling in normal skin and in skin affected by hair growth disorders (androgenic alopecia, alopecia areata) will provide important new knowledge into hair cycle biology and will rise a possibility to explore to explore BMP- antagonists for the treatment of these disorders.

背景资料：尽管致病机制不同，但两种最常见的毛发生长障碍（雄激素性脱发和斑秃）的特征在于毛囊小型化，静止期显著延长，毛发周期的生长期缩短和脱发。 在胚胎皮肤中触发毛囊诱导的分子信号，以及在出生后发育期间，在正常皮肤和受毛发生长障碍影响的皮肤中从静止到活跃生长和从活跃生长到消退的周期性转化，仍然知之甚少。 骨形态发生蛋白2/4（Bone morphogenic proteins 2/4，BMP 2/4）是转化生长因子-β/BMP超家族的成员，其特异性拮抗剂noggin能与BMP 2/4高亲和力结合并阻止BMP 2/4与BMP受体的相互作用，在控制外胚层衍生物（神经管、牙齿、羽毛）的诱导和调节发育过程中的细胞凋亡中发挥重要作用。 当BMP 2/4抑制形态发生并减小发育器官的大小时，BMP拮抗剂noggin刺激形态发生并下调BMP介导的凋亡。假设：通过其拮抗剂头蛋白中和BMP 2/4信号传导起着重要作用：i）在胚胎发生期间控制毛囊诱导，ii）在出生后皮肤中新毛发生长期的起始，iii）在受最常见毛发生长障碍影响的正常皮肤中调节脱发驱动的毛囊退化。目的：1）研究noggin基因敲除小鼠移植到SCID小鼠体内后胚胎皮肤毛囊的发育。 2)表征正常出生后C57 BL/6小鼠和人皮肤、受斑秃影响的C3 H/HeJ小鼠和受毛发生长障碍影响的人皮肤中毛囊周期期间头蛋白、BMP 2/4、BMP受体的表达。 3)确定noggin/BMP 2/4在体内和原位对小鼠和人皮肤中毛发周期的影响。 4)通过在K14和多功能蛋白聚糖启动子的控制下产生头蛋白过表达小鼠来确定头蛋白在皮肤中的体内功能。重要性：研究noggin和BMP 2/4作为正常皮肤和受毛发生长障碍（雄激素性脱发、斑秃）影响的皮肤中毛囊诱导和周期的推定调节剂的体内功能将为毛发周期生物学提供重要的新知识，并将增加探索BMP拮抗剂治疗这些疾病的可能性。