The Helios Gene in Development and Homeostasis of Skin

Helios 基因在皮肤发育和稳态中的作用

• 批准号: 7468029
• 负责人: BRUCE A MORGAN
• 金额: $ 36.04万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7468029
• 关键词: Acute; Alleles; Basement membrane; Binding Proteins; Cells; Chromatin Remodeling Factor; Defect; Development; Dominant-Negative Mutation; Embryo; Epidermis; Epithelial; Epithelium; Event; Exhibits; Family member; Gene Expression; Gene Family; Generations; Genes; Genetic; Goals; Growth; Hair follicle structure; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Integumentary system; Life; Lymphoid; Maintenance; Mouse Strains; Mus; Natural regeneration; Numbers; Plant Roots; Play; Population; Process; Proteins; Regulation; Role; Signal Pathway; Skin; Stem cells; Stratum Basale; Surface Ectoderm; System; Testing; Thinking; Time; Tissues; Transgenic Mice; Travel; appendage; base; cell type; epidermis cell; improved; in vivo; keratin 14, K14; keratinocyte; member; postnatal; progenitor; promoter; recombinase; research study; response

DESCRIPTION (provided by applicant): Homeostasis of the skin and its appendages relies on the continuous renewal of the epidermis and periodic renewal of the hair follicle epithelium throughout life from stem cells resident in these epithelia. While progress has been made in identifying these cells, the genetic mechanisms that regulate their specification as stem cells and the subsequent differentiation of their progeny to form the constituent cell types of the skin and its appendages in an orderly fashion remain poorly understood. This project examines the role of Helios, a member of the Ikaros gene family, in this process. The Ikaros family genes are critical to the development of hematopoietic stem cells and the subsequent progression of their progeny through the lineages that give rise to the lymphoid system. Our preliminary studies show that Helios is expressed in skin and interference with its function leads to profound defects in skin development and differentiation. It is our hypothesis that Helios activity is critical to the specification of stem cells in the skin and its appendages and to the orderly differentiation of their progeny. This project will test the role of Helios in development of the skin and its appendages. We will characterize the expression of Helios in more detail. A floxed allele of Helios will be employed in conjunction with ere recombinase lines to delete Helios function in different cell types in the epidermis and follicular epithelium of transgenic mice. This will allow us to identify critical time periods and cell types in which Helios acts and to assess the proximal effects of altering Helios function. Cells with altered Helios function will be partially purified by FACS from mice that express fluorescent proteins in different cell types in the skin and used to identify the genes whose expression changes in response to acute changes in Helios activity. A subset of these genes that represent direct targets of the regulatory activity of Helios will also be identified. These studies will impact our understanding of the normal and abnormal development of the skin and its appendages and the function of this gene family in the specification and function of stem cells of the integument.

描述（由申请人提供）：皮肤及其附属物的体内平衡依赖于表皮的连续更新，以及整个生命中毛孔毛囊上皮的周期性更新。尽管在识别这些细胞方面取得了进展，但是调节其规格为干细胞的遗传机制以及后代的随后分化以形成皮肤的组成细胞类型及其以有序的方式的附属物，但仍知之甚少。该项目研究了Ikaros Gene家族成员Helios在此过程中的作用。 Ikaros家族基因对造血干细胞的发展至关重要，以及随后通过产生淋巴样系统的谱系的后代进展。我们的初步研究表明，Helios在皮肤和干扰其功能方面表达，导致皮肤发育和分化方面存在深远的缺陷。我们的假设是，Helios活性对于皮肤中的干细胞及其附属物的规格以及其后代的有序分化至关重要。该项目将测试Helios在皮肤发育及其附属物中的作用。我们将更详细地表征Helios的表达。将与ERE重组酶系结合使用Helios的flox等位基因，以删除helios在表皮和转基因小鼠表皮和卵泡上皮的不同细胞类型中的功能。这将使我们能够确定Helios行为的关键时间和细胞类型，并评估改变Helios功能的近端效果。 HELIOS功能改变的细胞将由来自皮肤不同细胞类型中荧光蛋白的小鼠的FACS部分纯化，并用于鉴定其表达在响应Helios活性急性变化时的表达变化的基因。这些基因代表HELIOS调节活性的直接靶标的子集也将被识别。这些研究将影响我们对皮肤正常和异常发育及其附属物的理解以及该基因家族在外皮干细胞的规范和功能中的功能。