FUNCTIONS OF NOGGIN AND SMAD1/5 IN HAIR GROWTH CONTROL

描述(由申请人提供)： 背景：骨形态发生蛋白(BMPs)在包括皮肤在内的多种器官发育过程中，对细胞的增殖、分化和凋亡起着重要的调控作用。BMP信号是通过BMPs与BMP受体复合体(BMPR-IA/IB，BMPR-II)结合而激活的。在细胞外空间，BMP信号受BMP拮抗剂noggin的调节，它以高亲和力结合BMP-2/4/7，阻止它们与细胞表面的BMP受体相互作用。BMP-Smad通路是介导BMP在发育和出生后生长过程中作用的主要信号机制。BMP-Smad途径包括依赖于BMPRI的Smad1或Smad5转录因子的磷酸化，它们分别与Smad4转录共激活因子形成复合体，然后转位到细胞核中，调节BMP靶基因的转录。 BMPS、Noggin、Smad1和Smad5在毛囊发育和周期中广泛表达于毛囊上皮和间质。然而，由于noggin、Smad1或Smad5基因敲除小鼠的胚胎致死性，它们在控制毛囊细胞增殖、分化和凋亡方面的作用仍然很大程度上尚不清楚。 根据我们的初步数据，我们假设BMP在不同毛囊中作用的空间和时间特异性是由Nogin依赖的BMP受体信号强度以及Smad1和Smad5转录调控因子的不同招募决定的。 目的：1)以noggin转基因小鼠为模型，研究毛囊上皮和(或)间充质中BMP信号的普遍抑制对毛囊形态发生、毛囊周期和毛发色素形成的影响。 2)利用Smad1和Smad5活性缺失的基因工程小鼠，阐明Smad1和Smad5转录调控因子在BMP信号转导毛囊形态发生和毛囊周期中的作用。 3)确定Smad1和Smad5的下游靶点，它们介导BMP-Smad通路和其他参与调节毛囊形态发生、周期和毛发色素形成的受体信号系统之间的串扰。 意义：这项研究将为BMPs noggin调节头发生长的机制提供进一步的见解。和Smad1/5，并将导致识别新的重要靶分子，这些分子介导BMP信号对毛囊细胞的影响。这个项目的成功实现将有助于进一步了解不同脱发情况的病理生物学，并可能为使用BMP激动剂或拮抗剂治疗脱发提供新的策略。

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.