KERATINS, WOUND REEPITHELIZATION, AND HAIR FOLLICLE CYCLING

角蛋白、伤口上皮再生和毛囊循环

• 批准号: 7748983
• 负责人: Pierre Coulombe
• 金额: $ 41.43万
• 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 2011-08-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7748983
• 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，它们以 10-12nm 的细胞质网络形式存在 宽中间丝（IP）。它们由哺乳动物中的一个保守基因大家族编码， > 50 个个体成员分为两种序列类型。对杂聚物的严格要求- 细丝组装过程中 I 型和 II 型角蛋白的化是疼痛/visetranscriptional 的基础 角蛋白基因的调节。此外，个体对在组织类型和分化方面受到调节- 具体方式。阐明角蛋白多样性和差异分布背后的基本原理 提供了对上皮生物学、健康和疾病的新见解的希望。角蛋白 IP 具有弹性 然而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多种上皮脆性的基础 状况。此外，角蛋白 IP 还可调节细胞对特定促凋亡信号的反应，控制 细胞和组织的生长，以及膜蛋白在简单上皮细胞中的路径。今年已经是第九个年头了 该项目以角蛋白 16 和 17 为中心，它们在所有上皮附属物中组成型表达 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。下一个时期我们将重点关注非机械领域 皮肤上皮细胞中含有 K14、K16 和 K17 的细丝的功能，特别强调 上皮细胞存活（目标 1），通过调节蛋白质合成控制上皮细胞生长（目标 2）， 及其体内调节的表征（目标 3）。该提案实质上借鉴了 与小鼠缺乏角蛋白 17 相关的后果，导致继发性毛发循环缺陷 毛基质上皮细胞的过早凋亡以及与相关的胚胎伤口闭合缺陷 伤口边缘活化的上皮细胞尺寸较小。因为 K17 无效表型可以通过以下方式缓解： 由于角蛋白16和新发现的角蛋白17n的存在，我们还将生产小鼠品系 实现 K7n-K17-K16 基因簇的时间和空间控制失活（目标 4）。作为 因此，该项目将进一步了解角蛋白的特性以及在健康和疾病中的功能。