KERATINS, WOUND REEPITHELIZATION, AND HAIR FOLLICLE CYCLING

角蛋白、伤口上皮再生和毛囊循环

• 批准号: 7564744
• 负责人: Pierre Coulombe
• 金额: $ 40.86万
• 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/7564744
• 关键词: Apoptosis; Apoptotic; Binding; Binding Proteins; Biochemistry and Cellular Biology; Biology; Cell Survival; Cells; Code; 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; Pliability; Post-Translational Protein Processing; Property; Protein Biosynthesis; Proteins; Psoriasis; Regulation; Role; Route; Signal Transduction; Signaling Protein; Simple Epithelium; Skin; Skin Carcinoma; Skin Tissue; Tissues; UV Radiation Exposure; appendage; base; cell growth; extracellular; in vivo; insight; member; mouse genome; mouse model; novel; response; scaffold; wound

Keratins are abundant proteins in epithelial cells, in which they occur as a cytoplasmic network of 10-12nm 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 heteropolymer- ization of type I and type II keratin proteins during filament assembly underlies the pain/visetranscriptional 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 (Aim1), control of epithelial cell growth through regulation of protein synthesis (Aim 2), and the characterizationof their regulation in vivo (Aim 3). The proposal draws substantially from the consequences associatedwith lack of keratin 17 in mouse, which results in hair cycling defects secondaryto the untimely apoptosis of hair matrix epithelial cells, and in embryonic wound closure defects correlatingwith 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 indisease.

角蛋白是上皮细胞中丰富的蛋白质，在上皮细胞中以10- 12 nm的胞质网络存在 宽中间丝（IP）。它们由哺乳动物中的一大家族保守基因编码， > 50个单独的成员分为两个序列类型。对杂聚物的严格要求- I型和II型角蛋白在细丝组装过程中的化是疼痛/视觉转录的基础。 角蛋白基因的调节。此外，个体对在组织类型和分化中受到调节- 具体方式。阐明角蛋白多样性和差异分布背后的基本原理 为上皮生物学、健康和疾病提供了新的见解。角蛋白IP具有弹性 但柔韧的支架赋予上皮细胞维持机械和非机械的能力， 压力改变角蛋白编码序列的遗传突变是几种上皮脆性的基础 条件此外，角蛋白IP调节细胞对特异性促凋亡信号的反应， 细胞和组织生长，以及简单上皮细胞中膜蛋白的路由。今年是第九个年头， 该项目围绕角蛋白16和17展开，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、紫外线照射和其他挑战时，以及在 牛皮癣和皮肤癌等疾病。在接下来的时间里，我们将重点关注非机械 K14-，K16-和K17-含有丝在皮肤上皮细胞中的功能，特别强调 上皮细胞存活（Aim 1），通过调节蛋白质合成控制上皮细胞生长（Aim 2）， 以及它们在体内调节的特征（目的3）。该提案大量借鉴了 与小鼠缺乏角蛋白17相关的后果，这导致继发于 毛基质上皮细胞的过早凋亡，以及胚胎创伤闭合缺陷伴发 伤口边缘的活化上皮细胞较小。由于K17无效表型通过以下方式得到缓解 角蛋白16和新发现的角蛋白17 n的存在，我们还将产生一种小鼠品系， 能够在时间和空间上控制K7 n-K17-K16基因簇的失活（目的4）。作为 因此，该项目将进一步加深我们对角蛋白的性质和在健康和疾病中的功能的理解。