Cellular Senescence in the Pathogenesis of Benign Prostatic Hyperplasia

描述（由申请人提供）：细胞衰老限制了人类细胞的增殖，可以由各种细胞改变引起，包括内在的和外在的。随着年龄的增长，衰老细胞在人体组织中积累，包括前列腺。这些衰老细胞的功能发生了改变，包括促炎细胞因子的表达增加，从而改变邻近细胞的功能。良性前列腺增生（BPH）是老年男性最常见的病理。根据我们发表的研究，我们假设BPH组织中上皮细胞亚群的衰老导致细胞因子和生长因子的释放，这些细胞因子和生长因子通过直接和间接的作用，驱动邻近非衰老上皮细胞和基质细胞的增殖增加，最终导致衰老男性前列腺组织的生长。我们建议描述细胞衰老促进良性前列腺增生的机制。提出了两个具体目标。在特异性目标1中，我们将在体外和体内研究导致前列腺上皮衰老的潜在细胞改变；测定衰老上皮细胞体外表达的细胞因子和生长因子类型；评估这些相同的蛋白质在体内BPH组织中的表达水平是否升高，并定量评估这些细胞因子和生长因子在体内细胞水平上与衰老标志物（包括关键的细胞周期调节蛋白，如p21和p16）共表达的程度。在Specific Aim 2中，我们将使用前列腺上皮细胞和基质细胞的原代培养，反应性基质模型系统和转基因模型来检查已鉴定的细胞因子/生长因子的生物活性，并模拟这些因子在BPH中增加的潜在自分泌和旁分泌活性。此外，我们将建立转基因小鼠上皮衰老模型，并在该小鼠模型中检测上皮衰老的生物学影响。良性前列腺增生在老年男性中引起相当大的发病率，高达30%的男性需要治疗这种疾病，每年在这种疾病的医疗和手术治疗上花费超过10亿美元。这些研究将为我们理解细胞衰老在这一常见疾病发病机制中的作用做出根本性的贡献，并导致更有效的预防治疗和医学治疗。公共卫生相关性：良性前列腺增生会阻塞尿路，在老年男性中引起相当大的发病率，高达30%的男性在一生中的某个时候需要治疗这种疾病，每年在这种疾病的医疗和手术治疗上花费超过10亿美元。我们相信，这些研究将对我们了解这种常见疾病的原因作出根本性贡献，从而导致更有效的预防治疗和医学治疗。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Benign prostatic hyperplasia causes considerable morbidity in older men by blocking the urinary tract and up to 30% of men will require treatment for this condition at some time in their lives, with more than one billion dollars spent on the medical and surgical treatment of this disease annually. We believe these studies will make a fundamental contribution to our understanding the causes of this common disease and by doing so lead to more effective preventive treatments and medical therapies.