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EPITHELIAL DIFFERENTIATION: COMPARISON OF SKIN & THYMUS

上皮分化：皮肤比较

基本信息

批准号：
3153416
负责人：
KAY H SINGER
金额：
$ 9.49万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-12-01 至 1987-11-30
项目状态：
已结题

项目摘要

Keratinizing epithelia comprise many important tissues of the body and have been the subject of cell-biologic, genetic and biochemical investigation for most of this century. In recent years, development of techniques for in vitro propagation of nontransformed epidermal keratinocytes has stimulated their use as models for the study of regulation of cell differentiation. This proposal is designed to take advantage of epidermal culture techniques to investigate in parallel the regulation of differentiation of normal human epidermis, a tissue in which the in vivo differentiation program is known, and thymic epithelium, a tissue in which less is known about the program of differentiation. Epithelial specific monoclonal antibodies which in vivo define distinct compartments of both epidermis and thymic epithelium, will be used to establish the pathway of differentiation within the epithelial component of the thymus. Regulation of differentiation of both epidermis and thymic epithelium by calcium, epidermal growth factor, steroids, vitamin A, and other agents will be studied. Evidence suggests that epidermis and thymus share a special relationship with T lymphocytes. Epidermis has been postulated as a site of extra-thymic T cell maturation. This possibility will be examined in cocultivation experiments. Immunoincompetent T cell precursors will be cultured with human epidermal keratinocytes and also with supernatants from epidermal cultures and examined for changes in cell surface phenotype, expression of markers of T cell activation (4F2, transferrin receptor, Ia-like antigens), and acquisition of functional capability (response to mitogens and to foreign histocompatibility antigens). Patients with autoimmune disease often show abnormalities in immunoregulatory T cells which may be due to aberrant epithelial-T cell interaction. Sera from patients with autoimmune diseases also often show cross reactive binding on thymus and skin. In the autoimmune disease pemphigus, skin lesions are the result of a loss of cell-cell adhesion mediated by plasminogen activator stimulated by autoantibody. The potential role for plasminogen activator in aberrant function of thymic epithelium by disruption of cell-cell interaction will be examined. It is expected that these studies will provide insight into the basic processes of regulation of cellular differentiation and cell-cell interaction between epidermal and lymphoid cells, as well as aberrant interaction in pathologic states particularly autoimmune disorders.

角化上皮细胞包括身体的许多重要组织，一直是细胞生物学、遗传学和生物化学研究的主题在这个世纪的大部分时间里。近年来，非转化表皮角质形成细胞的体外增殖刺激了它们作为研究细胞调节的模型的用途，分化该提案旨在利用表皮培养技术，以平行研究正常人表皮的分化，在体内的组织，分化程序是已知的，胸腺上皮是其中对微分程序知之甚少。上皮特异性单克隆抗体，其在体内限定了两者的不同区室，表皮和胸腺上皮，将用于建立在胸腺的上皮成分内的分化。调控表皮和胸腺上皮的分化，表皮生长因子，类固醇，维生素A和其他药物将被研究了有证据表明，表皮和胸腺共享一种特殊的与T淋巴细胞的关系表皮被认为是胸腺外T细胞的成熟。这种可能性将在共培养实验免疫活性T细胞前体将是与人表皮角质形成细胞以及来自表皮培养物并检查细胞表面表型的变化， T细胞活化标志物（4F 2，转铁蛋白受体， IA样抗原）和获得功能性能力（对有丝分裂原和外源组织相容性抗原）。患者自身免疫性疾病通常表现为免疫调节性T细胞异常这可能是由于异常的上皮-T细胞相互作用。血清自身免疫性疾病患者也经常表现出交叉反应性结合，胸腺和皮肤。在自身免疫性疾病天疱疮，皮肤病变是纤溶酶原激活剂介导的细胞间粘附丧失的结果受自身抗体刺激。纤溶酶原激活剂的潜在作用在细胞-细胞破坏导致胸腺上皮功能异常中互动将被审查。预计这些研究将提供了对细胞调节的基本过程的洞察力，表皮和淋巴细胞之间的分化和细胞-细胞相互作用细胞，以及病理状态下的异常相互作用，自身免疫性疾病