Cytokines Stimulate Prostate Epithelial Proliferation

描述（由申请人提供）：慢性炎症与癌症的长期关联导致发现炎症介质如白细胞介素可促进肿瘤生长。这些炎症介质通常被认为具有炎症的主要作用，并且它们对肿瘤细胞生长的作用通常被认为是非特异性生长作用。然而，我们目前的证据表明，炎症介质实际上发挥了以前未认识到的作用，促进上皮生长在正常前列腺发育。我们的初步数据显示，在没有细胞炎症的情况下，炎症介质在发育中的前列腺中的稳健表达，并证明这些炎症介质促进上皮生长和p63+上皮细胞的选择性扩增。我们还将表明，白细胞介素-1受体缺陷的小鼠表现出显着破坏前列腺发育和炎症反应的增生。这些观察结果使我们提出了一个具有挑衅性的论点，即炎症介质对慢性炎症和癌症中上皮增殖的影响是正常发育过程中其作用的重复。我们提出了两个具体的目标，以解决特定的假设，IL-1 R介导的信号刺激上皮祖细胞和间充质细胞的增殖，在发展中的前列腺。目的1：研究IL-1配体在前列腺发育过程中的表达及作用。将使用药理学操作在体内和体外进行研究，以确定这些炎症介质在前列腺发育过程中促进上皮细胞增殖和祖细胞扩增的作用。目的2：研究IL-1 R LOF对前列腺发育的影响。我们将通过检测IL-1-R1的遗传破坏对前列腺发育、上皮和间充质增殖以及祖细胞扩增的影响来测试IL-1 R在前列腺生长中的生物学相关性。我们希望这些研究能够表明，所谓的炎症介质实际上在调节祖细胞增殖中起着核心作用。如果正确的话，这将表明，炎症介质的白细胞募集到损伤部位的表达促进上皮祖细胞增殖的再生修复过程的一部分。这些研究有可能彻底改变对前列腺细胞因子作用的理解，深入了解慢性炎症产生增生和异型增生的机制，并为预防肿瘤进展的治疗干预提供科学依据。 公共卫生相关性 我们希望这些研究能够表明，所谓的炎症介质实际上在调节祖细胞增殖中起着核心作用。如果正确的话，这将表明，炎症介质的白细胞募集到损伤部位的表达促进上皮祖细胞增殖的再生修复过程的一部分。这些研究有可能彻底改变对前列腺细胞因子作用的理解，深入了解慢性炎症产生增生和异型增生的机制，并为预防肿瘤进展的治疗干预提供科学依据。

DESCRIPTION (provided by applicant): The long-standing association of chronic inflammation with cancer has led to the discovery that inflammatory mediators such as interleukins can promote tumor growth. These inflammatory mediators are generally conceived as having a primary role inflammation and their effects on tumor cell growth has generally been considered a non-specific growth effect. However, we present evidence that inflammatory mediators actually exert a previously unrecognized role in promoting epithelial growth during normal prostate development. Our preliminary data show robust expression of inflammatory mediators in the developing prostate in the absence of cellular inflammation and demonstrate that these inflammatory mediators promote epithelial growth and a selective expansion of p63+ epithelial cells. We will also show that mice deficient in interleukin-1 receptor exhibit significantly disrupted prostate development and hyperplastic response to inflammation. These observations lead us to propose the provocative thesis that the effects of inflammatory mediators on epithelial proliferation in chronic inflammation and cancer are a re-iteration of their actions during normal development. We propose two specific aims to address the specific hypothesis that IL-1R mediated signaling stimulates proliferation of epithelial progenitor cells and mesenchyme in the developing prostate. Aim 1: Characterize the expression and actions of IL-1 ligands during prostate development. Studies will be performed both in vivo and in vitro using pharmacologic manipulation to determine the role of these inflammatory mediators in promoting epithelial proliferation and expansion of progenitor cells during prostate development. Aim 2: Characterize the effect of IL-1R LOF on prostate development. We will test the biologic relevance IL-1R in prostate growth by examining the effect of genetic disruption of IL1-R1 on prostate development, epithelial and mesenchymal proliferation, and progenitor cell expansion. We expect these studies to show that so-called inflammatory mediators actually play a central role in regulating progenitor cell proliferation. If correct, this would suggest that expression of inflammatory mediators by leukocytes recruited to a site of injury promotes epithelial progenitor cell proliferation as part of the regenerative repair process. These studies have the potential to revolutionize the understanding of cytokine action in the prostate, provide insights into the mechanisms by which chronic inflammation produces hyperplasia and dysplasia, and provide the scientific basis for therapeutic interventions to forestall progression to neoplasia. PUBLIC HEALTH RELEVANCE We expect these studies to show that so-called inflammatory mediators actually play a central role in regulating progenitor cell proliferation. If correct, this would suggest that expression of inflammatory mediators by leukocytes recruited to a site of injury promotes epithelial progenitor cell proliferation as part of the regenerative repair process. These studies have the potential to revolutionize the understanding of cytokine action in the prostate, provide insights into the mechanisms by which chronic inflammation produces hyperplasia and dysplasia, and provide the scientific basis for therapeutic interventions to forestall progression to neoplasia.