Cellular Senescence in the Pathogenesis of Benign Prostatic Hyperplasia

摘要 细胞衰老限制了人类细胞的增殖，并可由多种细胞因子诱导 改变，内在的和外在的。衰老细胞在人体组织中积累，包括前列腺， 随着年龄的增长。这些衰老细胞的功能发生了变化，包括表达增加的 能改变邻近细胞功能的促炎细胞因子。良性前列腺增生(BPH)是 这是老年男性最常见的一种病理。根据我们已发表的研究，我们假设 BPH组织中一组上皮细胞的衰老导致细胞因子和生长因子的释放， 通过直接和间接作用，促进邻近非衰老上皮细胞的增殖，并 老年男性的间质细胞和最终的前列腺组织生长。我们建议对这些机制进行描述 通过细胞衰老促进良性前列腺增生症的发展。两个具体目标 都被提出了。在特定的目标1中，我们将研究导致前列腺癌的潜在细胞变化。 细胞因子和生长因子在体外和体内的衰老 在体外培养衰老的上皮细胞；评估这些相同的蛋白是否在 并定量评估这些细胞因子在体内共表达的程度和 体内细胞水平的生长因子与衰老的标志物，包括关键的细胞周期调节因子 蛋白质如p21和p16。在特定的目标2中，我们将使用前列腺上皮和间质的原代培养 细胞、反应间质模型系统和转基因模型来检测细胞的生物学活性 确定细胞因子/生长因子，并模拟这些因子的潜在自分泌和旁分泌活性 在体内的良性前列腺增生症中增加。此外，我们还将建立转基因小鼠上皮细胞衰老模型。 并在这个小鼠模型中检查上皮衰老的生物学影响。良性前列腺增生症 在老年男性中造成相当大的发病率，高达30%的男性需要治疗这种疾病，以及 每年在这种疾病的内科和外科治疗上花费超过10亿美元。这些 这些研究将为我们理解细胞衰老在细胞衰老中的作用做出基础性贡献。 这一常见病的发病机制并导致更有效的预防性治疗和医学治疗。

ABSTRACT Cellular senescence limits the proliferation of human cells and can be induced by a variety of cellular alterations, both intrinsic and extrinsic. Senescent cells accumulate in human tissues, including the prostate, with increasing age. These senescent cells have altered function, including increased expression of proinflammatory cytokines that can alter the function of adjacent cells. Benign prostatic hyperplasia (BPH) is the single most common pathology of aging men. Based on our published studies we hypothesize that senescence of a subset of epithelial cells in BPH tissue leads to release of cytokines and growth factors that, through direct and indirect actions, drives increased proliferation of adjacent non-senescent epithelial cells and stromal cells and ultimately prostatic tissue growth in aging men. We propose to characterize the mechanisms by which cellular senescence can promote the development of benign prostatic hyperplasia. Two Specific Aims are proposed. In Specific Aim 1, we will examine the underlying cellular alterations leading to prostatic epithelial senescence in vitro and in vivo; determine the types of cytokines and growth factors expressed by senescent epithelial cells in vitro; evaluate whether these same proteins are expressed at increased levels in BPH tissue in vivo and quantitatively evaluate the extent to which there is coexpression of these cytokines and growth factors at the cellular level in vivo with markers of senescence, including key cell cycle regulator proteins such as p21 and p16. In Specific Aim 2 we will use primary cultures of prostatic epithelial and stromal cells, the reactive stroma model system and transgenic models to examine the biological activities of the identified cytokines/growth factors and model potential autocrine and paracrine activities of those factors that are increased in BPH in vivo. In addition, we will establish a transgenic mouse model of epithelial senescence and examine the biological impact of epithelial senescence in this mouse model. Benign prostatic hyperplasia causes considerable morbidity in older men, with up to 30% of men requiring treatment for this condition, and with more than one billion dollars spent on the medical and surgical treatment of this disease annually. These studies will make a fundamental contribution to our understanding of the role of cellular senescence in the pathogenesis of this common disease and lead to more effective preventive treatments and medical therapies.