Role Of Ectodysplasin-a In Skin Appendage Formation

外胚层增生素-a 在皮肤附属器形成中的作用

基本信息

批准号：
7732268
负责人：
David Schlessinger
金额：
$ 41.62万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

X-linked anhidrotic ectodermal dysplasia (EDA) is the most frequently occurring of more than 175 ectodermal dysplasias affecting one or more skin appendages. The gene that is mutated to cause this disorder encodes a protein, which we have named ectodysplasin-A, has a single transmembrane region with collagenous and TNF-ligand segments in a long extracelliular carboxyterminal tail. Because individuals with EDA have sparse hair, rudimentary teeth, and few sweat glands, the gene is likely involved at an early point in development. We demonstrated that the Tabby mouse, which has many of the features observed in human EDA, is specifically mutated in the corresponding mouse gene. We found that provision of DNA encoding a variant of ectodysplasin in embryonic mice rstores hair follicles and sweat glands. We also have characterized eye phenotypes of Tabby mice including blindness and inflammation susceptibility, and they are also reversed by supplementation with the same isoform. In additional studies to look at the final phases of hair follicle development, we are studying the human disease Cartilage Hair Hypoplasia in a mouse model. These studies should facilitate attempts to maintain or reform hair follicles. In mechanistic studies, we have shown that EDA acts through the powerful NF-kB signaling pathway to activate four major target pathways, including the unanticipated involvement of lymphotoxin-beta, a molecule previously only known to help form immune system organs. EDA and all of the downstream pathways are required to continue the development of already initiated skin appendages. Work is continuing to analyze the process and its regulation in detail in mouse models. The models include the study of mice bearing skin-specific transgenes encoding Dkk4, which appears to regulate EdA expression; Shh, which is a major target of EDA; Nemo, a bridge to the NF-kB pathway; and Troy, a possible receptor for EDA action.

X连锁的鼻鼻外胚性发育不良（EDA）是影响一个或多个皮肤附属物的175多个超过175个超胚层发育不良的发生。引起该疾病的突变的基因编码一种蛋白质，我们称之为胞倍倍倍肌蛋白A具有一个单个跨膜区域，在长的细胞外羧基末端尾巴中具有胶原式和TNF-Ligand片段。由于EDA患者的头发稀疏，牙齿稀疏，汗腺很少，因此该基因可能在发育的早期参与。我们证明，在相应的小鼠基因中特异性突变的Tabby小鼠具有许多在人EDA中观察到的特征。我们发现，在胚胎小鼠中编码一种胞质成骨蛋白变体的DNA提供了毛囊和汗腺。我们还表征了塔比小鼠的眼表型，包括失明和炎症敏感性，并且还通过补充相同的同工型来逆转它们。在研究毛囊发育的最终阶段的其他研究中，我们正在研究小鼠模型中的人类疾病软骨性发育不全。这些研究应促进维持或改革毛囊的尝试。在机械研究中，我们已经表明，EDA通过强大的NF-KB信号通路起作用，激活四个主要目标途径，包括淋巴毒素-ABETA的意外参与，淋巴细胞毒素β，这是一种以前仅已知有助于形成免疫系统器官的分子。 EDA和所有下游途径都必须继续开发已经引发的皮肤附属物。工作正在继续分析鼠标模型中的过程及其调节。这些模型包括对编码DKK4的皮肤特异性转基因的小鼠的研究，该小鼠似乎调节EDA表达。 SHH，这是EDA的主要目标； Nemo，通往NF-KB途径的桥梁；和特洛伊（Troy），是EDA作用的可能受体。