FUNCTIONS OF NOGGIN AND SMAD1/5 IN HAIR GROWTH CONTROL

描述（由申请人提供）： 背景资料：骨形态发生蛋白（BMPs）在包括皮肤在内的许多器官发育过程中对细胞增殖、分化和凋亡的调控起着关键作用。BMP信号传导通过BMP与BMP受体复合物的结合而被激活，所述BMP受体复合物由I型和II型BMP受体（BMPR-IA/IB，BMPR-II）组成。在细胞外空间，BMP信号传导由BMP拮抗剂头蛋白调节，其以高亲和力结合BMP-2/4/7并阻止它们与细胞表面BMP受体相互作用。BMP-Smad信号通路是BMP在发育和出生后生长过程中发挥作用的主要信号通路。BMP-Smad途径包括BMPRI依赖性的Smad 1或Smad 5转录因子磷酸化，然后它们各自与Smad 4转录辅激活因子形成复合物，随后易位到细胞核中以调节BMP靶基因的转录。 BMP、noggin、Smad 1和Smad 5广泛表达于毛囊的上皮和间充质中，并参与毛囊的发育和周期。然而，由于noggin，Smad 1或Smad 5基因敲除小鼠的胚胎致死性，它们在毛囊细胞增殖，分化和凋亡的控制中的作用在很大程度上仍然未知。 基于我们的初步数据，我们假设BMP在不同毛囊隔室中的作用的空间和时间特异性由通过BMP受体的信号传导的头蛋白依赖性幅度和Smad 1和Smad 5转录调节因子的差异募集决定。 目的：1）使用noggin转基因小鼠作为模型，确定毛囊上皮和/或间充质中BMP信号传导的一般抑制对毛囊形态发生、周期和毛发色素沉着的影响。 2)描述Smad 1和Smad 5转录调节因子在介导BMP信号传导对毛囊形态发生和周期的影响中的作用，使用Smad 1或Smad 5活性丧失的基因工程小鼠。 3)确定Smad 1和Smad 5的下游靶点，这些靶点介导BMP-Smad通路与其他参与调节毛囊形态发生、周期和毛发色素沉着的受体信号系统之间的串扰。 意义：本研究将为进一步了解骨形成蛋白noggin调控毛发生长的机制提供理论依据。和Smad 1/5，并将导致新的重要的靶分子介导的BMP信号对毛囊细胞的影响的鉴定。该项目的成功实现将有助于进一步了解不同脱发状况的病理生物学，并可能为使用BMP激动剂或拮抗剂进行治疗提供新的策略。

DESCRIPTION (provided by applicant): Background: Bone morphogenetic proteins (BMPs) play pivotal roles in the control of cell proliferation, differentiation, and apoptosis during development of many organs including skin. BMP signaling is activated by binding of the BMPs to BMP receptor complex that consists of type I and II BMP-receptors (BMPR-IA/IB, BMPR-II). In extracellular space, BMP signaling is modulated by BMP-antagonist noggin, which binds BMP-2/4/7 with high affinity and prevents their interaction with cell surface BMP receptors. BMP-Smad pathway is a major signaling mechanism that mediates BMP effects during development and postnatal growth. BMP-Smad pathway includes BMPRI-dependent phosphorylation of Smadl or Smad5 transcription factors, each of them then form the complex with Smad4 transcriptional co-activator followed by translocation into the nucleus to regulate transcription of BMP target genes. BMPs, noggin, Smad1 and Smad5 are broadly expressed in the hair follicle epithelium and mesenchyme during its development and cycling. However, due to embryonic lethality of the noggin, Smad1 or Smad5 knockout mice, their roles in the control of cell proliferation, differentiation and apoptosis in the hair follicle remain largely unknown. Based on our preliminary data, we hypothesize that spatial and temporal specificity of BMP effects in distinct hair follicle compartments is determined by noggin-dependent magnitude of signaling through BMP receptors and by differential recruitment of the Smad1 and Smad5 transcriptional regulators. Purpose: 1) Define the effects of general inhibition of BMP signaling in hair follicle epithelium and/or mesenchyme on hair follicle morphogenesis, cycling and hair pigmentation using noggin transgenic mice as models. 2) Delineate the roles of Smad1 and Smad5 transcriptional regulators in mediating the effects of BMP signaling on hair follicle morphogenesis and cycling using genetically engineered mice with loss of the Smad1 or Smad5 activity. 3) Identify the downstream targets of Smad1 and Smad5 that mediate cross-talk between the BMP-Smad pathway and other receptor signaling systems involved in regulating hair follicle morphogenesis, cycling and hair pigmentation. Significance: This study will provide further insights into the mechanisms of hair-growth regulation by BMPs, noggin. and Smad1/5 and will lead to the identification of new important target molecules that mediate the effects of BMP signaling on hair-follicle cells. Successful realization of this project will help in further understanding the pathobiology of different hair-loss conditions and may provide new strategies for their therapy using BMP agonists or antagonists.