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

背景：尽管发病机制不同，但两种最常见的毛发生长障碍（雄激素性脱发和斑秃）的特征是毛囊小型化，静止期明显延长，毛发周期生长期缩短，以及脱发。在正常皮肤和受毛发生长障碍影响的皮肤中，胚胎皮肤中触发毛囊诱导的分子信号，以及出生后发育过程中从静止到活跃生长和从活跃生长到退化的循环转化，仍然知之甚少。骨形态发生蛋白2/4 （BMP2/4）是转化生长因子- β /BMP超家族的成员，其特异性拮抗剂noggin与BMP2/4高亲和力结合并阻止其与BMP受体的相互作用，在控制外胚层衍生物（神经管、牙齿、羽毛）的诱导和发育过程中凋亡细胞死亡的调控中发挥重要作用。BMP2/4抑制形态发生并减小发育器官的大小，而BMP-拮抗剂noggin则刺激形态发生并下调BMP介导的细胞凋亡。假设：通过其拮抗剂noggin中和BMP2/4信号发挥重要作用：1)在胚胎发生过程中控制毛囊的诱导，2)在出生后皮肤中开始新的毛发生长阶段，3)在受大多数常见毛发生长障碍影响的正常皮肤中调节细胞凋亡驱动的毛囊退化。目的：1)研究noggin基因敲除小鼠胚胎皮肤移植到SCID小鼠体内的毛囊发育情况。2)表征正常出生后C57BL/6小鼠和人皮肤、斑秃影响的C3H/HeJ小鼠、毛发生长障碍影响的人皮肤毛囊循环过程中noggin、bmp /4、bmp受体的表达。3)确定noggin/BMP2/4在体内和原位对小鼠和人皮肤毛发周期的影响。4)在K14和versican启动子的控制下，通过培养noggin过表达小鼠，确定noggin在皮肤中的体内功能。意义：在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，研究noggin和BMP /4作为毛囊诱导和循环的推测调节剂的体内功能，将为头发周期生物学提供重要的新知识，并为探索BMP-拮抗剂治疗这些疾病提供可能性。

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.