Keratins, Wound Reepithelialization, and Hair Follicle Cycling

角蛋白、伤口上皮再生和毛囊循环

• 批准号: 7173039
• 负责人: Pierre Coulombe
• 金额: $ 43.27万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-20 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7173039
• 关键词: Apoptosis; Apoptotic; Binding; Binding Proteins; Biochemistry and Cellular Biology; Biology; Cell Survival; Cells; Closure; Code; Condition; Cytoskeleton; Defect; Disease; Embryo; Epithelial; Epithelial Cells; Epithelium; Family; Filament; Funding; Gene Cluster; Genes; Genetic Engineering; Grant; Growth; Hair; Hair follicle structure; Health; Histocompatibility Testing; Individual; Inherited; Injury; Intermediate Filaments; Keratin; Knockout Mice; Mammals; Mechanical Stress; Mechanics; Membrane Proteins; Mouse Strains; Mus; Mutation; Pain; Phenotype; Physiology; Post-Translational Protein Processing; Property; Protein Biosynthesis; Proteins; Psoriasis; Regulation; Role; Route; Secondary to; Signal Transduction; Signaling Protein; Simple Epithelium; Skin; Skin Carcinoma; Skin Tissue; Tissues; Transcriptional Regulation; UV Radiation Exposure; appendage; base; cell growth; concept; extracellular; in vivo; insight; member; mouse genome; mouse model; novel; response; scaffold; size; wound

DESCRIPTION (provided by applicant): Keratins are abundant proteins in epithelial cells, in which they occur as a cytoplasmic network of 10-12 nm wide intermediate filaments (IPs). They are encoded by a large family of conserved genes in mammals, with > 50 individual members partitioned into two sequence types. A strict requirement for the heteropolymerization of type I and type II keratin proteins during filament assembly underlies the pain/vise transcriptional regulation of keratin genes. In addition, individual pairs are regulated in a tissue-type and differentiation- specific manner. Elucidating the rationale behind the diversity and differential distribution of keratin proteins offers the promise of novel insight into epithelial biology, in health and disease. Keratin IPs act as resilient yet pliable scaffolds that endow epithelial cells with the ability to sustain mechanical and non-mechanical stresses. Inherited mutations altering the coding sequence of keratins underlie several epithelial fragility conditions. In addition, keratin IPs modulate the cell's response to specific pro-apoptotic signals, control of cell and tissue growth, and the routing of membrane proteins in simple epithelia. Now it its ninth year, this project is centered around keratins 16 and 17, which are constitutively expressed in all epithelial appendages and induced whenever skin tissue is subjected to injury, UV exposure, and other challenges, as well as in diseases such as psoriasis and skin carcinoma. During the next period we will focus on the non-mechanical functions of K14-, K16- and K17-containing filaments in skin epithelia, with a particular emphasis on epithelial cell survival (Aim 1), control of epithelial cell growth through regulation of protein synthesis (Aim 2), and the characterization of their regulation in vivo (Aim 3). The proposal draws substantially from the consequences associated with lack of keratin 17 in mouse, which results in hair cycling defects secondary to the untimely apoptosis of hair matrix epithelial cells, and in embryonic wound closure defects correlating with smaller size of activated epithelial cell at the wound edge. Because the K17 null phenotype is mitigated by the presence of keratin16 and the newly discovered keratin17n, we will also produce a mouse strain enabling the temporally- and spatially-controlled inactivation of the K7n-K17-K16 gene cluster (aim 4). As such, the project will further our understanding of keratin properties and function in health and in disease.

描述（由申请人提供）：角蛋白是上皮细胞中丰富的蛋白质，在上皮细胞中，角蛋白以10-12 nm宽的中间丝（IP）的细胞质网络形式存在。它们由哺乳动物中的保守基因的大家族编码，其中> 50个个体成员被分成两种序列类型。在细丝组装过程中，I型和II型角蛋白蛋白的异源聚合的严格要求是角蛋白基因的pain/vise转录调控的基础。此外，个体对以组织类型和分化特异性方式进行调节。阐明角蛋白的多样性和差异分布背后的基本原理，为健康和疾病中的上皮生物学提供了新的见解。角蛋白IP充当弹性但柔韧的支架，其赋予上皮细胞承受机械和非机械应力的能力。改变角蛋白编码序列的遗传突变是几种上皮脆性疾病的基础。此外，角蛋白IP调节细胞对特定促凋亡信号的响应、细胞和组织生长的控制以及简单上皮细胞中膜蛋白的路由。现在已经是第九个年头了，该项目以角蛋白16和17为中心，角蛋白16和17在所有上皮附属物中组成性表达，每当皮肤组织受到损伤，紫外线暴露和其他挑战以及牛皮癣和皮肤癌等疾病时都会诱导。在接下来的时间里，我们将重点关注皮肤上皮中含有K14、K16和K17的细丝的非机械功能，特别强调上皮细胞存活（目标1）、通过调节蛋白质来控制上皮细胞生长合成（目标2），以及它们在体内调节的特征（目标3）。该提议基本上来自与小鼠中缺乏角蛋白17相关的后果，其导致继发于毛基质上皮细胞的过早凋亡的毛发周期缺陷，以及与伤口边缘处活化上皮细胞的较小尺寸相关的胚胎伤口闭合缺陷。因为K17无效表型通过角蛋白16和新发现的角蛋白17 n的存在而减轻，我们还将产生能够在时间和空间上控制K7 n-K17-K16基因簇失活的小鼠品系（目的4）。因此，该项目将进一步了解角蛋白的特性和在健康和疾病中的功能。