Role of the PPARb in epithelial cell proliferation

PPARb 在上皮细胞增殖中的作用

• 批准号: 6633924
• 负责人: Jeffrey M Peters
• 金额: $ 21.15万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-15 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6633924
• 关键词: basal cell carcinoma; carcinogen testing; chemical carcinogen; chemical carcinogenesis; complementary DNA; cyclins; dimethylbenzanthracene; eicosanoid metabolism; enzyme activity; gene mutation; genetically modified animals; hyperplasia; ionizing radiation; keratinocyte; laboratory mouse; mutagen testing; mutagens; neoplasm /cancer genetics; nonsteroidal antiinflammatory agent; peroxisome proliferator activated receptor; phorbols; prostaglandin endoperoxide synthase; radiation carcinogen; radiation carcinogenesis; ultraviolet radiation

DESCRIPTION (provided by applicant): Since it was first identified as a member of the peroxisome proliferator-activated receptors (PPARs) in 1994, specific roles for the PPARI3 have remained elusive. Despite numerous roles elucidated for the PPARa and PPARy that contribute to diseases including hyperlipidemias, atherosclerosis, obesity, diabetes and cancer, the function of PPARb has remained a mystery. The recent phenotypical description of a PPARb-null mouse has provided the first direct, in vivo evidence that the PPARb is involved in epithelial cell proliferation. Topical application of the tumor promoter TPA causes enhanced epidermal cell proliferation in PPARb-null mice compared to controls suggesting that the hyperplastic response induced by TPA is attenuated by the PPARb. Further, the non-steroidal anti-inflammatory drug (NSAID), sulindac, inhibits TPA-induced inflammation and epidermal hyperplasia in wild-type mice and this effect is not found in similarly treated PPARb-null mice. This suggests that the beneficial effects of sulindac are modulated by the PPARb. The overall hypothesis of this proposal is that the PPARb3 is central to the epithelial cell proliferative response that results in skin tumor formation from genetic or chemical factors. A secondary hypothesis is that PPARb-null mice will be refractory to the influence of sulindac in preventing epidermal hyperplasia that contributes to skin tumor formation. The first specific aim is to develop three model systems to test these hypotheses. The first model will utilize crossing the PPARb-null mice with patched +1/- mice that are genetically more sensitive to ultraviolet or ionizing radiation-induced skin tumors. The second model will assess two-stage carcinogenicity in the PPARb-null mouse and the last model will characterize a keratinocyte culture system using cells from PPARb-null mice so that it can be utilized to further mechanistically define the role of the PPARb in the TPA-induced epidermal cell proliferative response. Since preliminary data indicate that PPARb attenuates TPA-induced COX-2 mRNA expression, the second specific aim will determine if PPARb-specific alterations in eicosanoid function contribute to the mechanisms of enhanced epidermal cell proliferation. The third specific aim will identify and initially characterize PPARbdependent gene expression in skin cells resulting from treatment with TPA. Results from this work will determine if PPARb influences epidermal cell proliferation that contribute to the incidence of skin cancer, determine if PPARb-dependent alterations in eicosanoid metabolism underlie enhanced cell proliferation induced by TPA in PPARb-null mice, and characterize PPARb target genes in epithelial cells.

描述（由申请人提供）：由于它首先被标识为成员 1994年过氧化物酶体增殖物激活受体（PPAR）的特异性受体 PPARI3的角色仍然难以捉摸。尽管阐明了许多角色 对于有助于包括高脂症在内的疾病的PPARA和PPARA， 动脉粥样硬化，肥胖，糖尿病和癌症，PPARB的功能 仍然是一个谜。 PPARB无效鼠标的最新表型描述 提供了第一个直接的体内证据，表明PPARB参与 上皮细胞增殖。肿瘤启动子TPA的局部应用 与PPARB无效小鼠相比 对照表明TPA诱导的增生响应已减弱 由PPARB。此外，非甾体类抗炎药（NSAID）， Sulindac，抑制TPA诱导的炎症和表皮增生 野生型小鼠，在类似处理的PPARB无效中找不到这种效果 老鼠。这表明Sulindac的有益作用是由 PPARB。该提议的总体假设是PPARB3是 上皮细胞增殖反应的中心，导致皮肤 由遗传或化学因子形成肿瘤。次要假设是 PPARB无效的小鼠将对苏莱达克的影响难治性 防止表皮增生，从而导致皮肤肿瘤的形成。这 第一个具体目的是开发三个模型系统来检验这些假设。 第一个模型将利用用修补的+1/ - 越过PPARB-NULL小鼠 遗传上对紫外线或电离更敏感的小鼠 辐射引起的皮肤肿瘤。第二个模型将评估两个阶段 PPARB无效小鼠中的致癌性和最后一个模型将表征 角质形成细胞培养系统使用来自PPARB无效小鼠的细胞，以便它可以是 用于进一步机械地定义了PPARB的作用 TPA诱导的表皮细胞增殖反应。由于初步数据 表明PPARB减弱TPA诱导的COX-2 mRNA表达，第二个 具体目标将确定eicosanoid的PPARB特异性改变是否 功能有助于增强表皮细胞增殖的机制。 第三个特定目的将识别并最初表征pPARBDETEMENT 用TPA治疗导致的皮肤细胞中的基因表达。结果 这项工作将确定PPARB是否影响表皮细胞的增殖 有助于皮肤癌的发生率，确定PPARB是否依赖 eicosanoid代谢的改变是增强细胞增殖的基础 TPA在PPARB无效小鼠中诱导，并表征了PPARB靶基因 上皮细胞。