GROWTH FACTORS AND THE BPH CHIMPANZEE MODEL

生长因子和 BPH 黑猩猩模型

• 批准号: 6502829
• 负责人: MITCHELL S. STEINER
• 金额: $ 10.92万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6502829
• 关键词: Pan; aging; animal colony; benign prostate hyperplasia; disease /disorder etiology; epidemiology; estrogens; growth factor; hormone regulation /control mechanism; longitudinal animal study; testosterone

DESCRIPTION (Adapted from the Applicant's Abstract): Benign prostatic hyperplasia (BPH) is the most common nonmalignant disease in men over 40 years of age of all races and cultures. BPH is the enlargement of the prostate as a consequence of the overproliferation of stromal and glandular elements. The etiology and natural history of BPH, however, remain obscure. Numerous studies support the role of aging, hormones, peptide growth factors, and genetic mutations in the onset and pathogenesis of BPH. Based on both current experimental and clinical data, a unifying hypothesis for the etiology of BPH was proposed: The initial stimulus for aberrant growth occurs when the epithelial or stromal cell has reached a critical threshold of accumulated genetic mutational events with aging and reverts to an embryonic clone. Under the permissive effects of androgen and estrogens, the embryonic clone acquires autonomous growth by the abnormal secretion peptide growth factors. Peptide growth factors directly mediate the epithelial and stromal interactions responsible for Phase I, the induction and maintenance of the BPH nodule. Androgens and estrogens probably play a more important role in Phase II, the diffuse acceleration of BPH nodular growth in later life. This working hypothesis will be tested in the chimpanzee, man's closest primate relative who shares 98% DNA sequence homology with humans, and like man develops spontaneous BPH, through the following Specific Aims: 1) To characterize Phase I and Phase II spontaneous BPH by cross sectional analysis of an aging chimpanzee colony; 2) To characterize Phase I and Phase II spontaneous BPH by longitudinal analysis of an aging chimpanzee colony; and 3) To determine the relationship of androgens and estrogens to peptide growth factors by experimentally inducing BPH in the chimpanzee by hormonal manipulation. The hypothesis that androgens and estrogens are permissive and that peptide growth factors are directly responsible for the abnormal epithelial and stromal interactions responsible for BPH will be tested in the aging chimpanzee by minimally invasive, survival approaches. More specifically, both the temporal and spatial expression of peptide growth factors[Transforming growth factor a (TGFa), Transforming growth factor b (TGFb) and basic fibroblast growth factor (bFGF)] and their receptors [Epidermal growth factor receptor (EGFR) and TGFb receptor type I and type II (TGFb RI and RII)] and their relationship to androgens (testosterone) and estrogens (estradiol and estrone) should provide important clues about the etiology and natural history of BPH. More importantly, these studies may hold future promise by serving as a basis to determine whether spontaneous BPH in the nonhuman primate may be modified by preventable or therapeutic manipulation which can be later applied to BPH in man.

描述（改编自申请人的摘要）：良性前列腺 增生（BPH）是40岁以上男性中最常见的非恶性疾病 各种种族和文化的年龄。 BPH是扩大的 前列腺由于基质和腺体过度增殖而导致 元素。 但是，BPH的病因和自然历史仍然晦涩难懂。 大量研究支持衰老，激素，肽生长的作用 BPH发作和发病机理中的因素和遗传突变。 基于 在当前的实验和临床数据上，这是一个统一的假设 提出了BPH的病因：异常生长的初始刺激 当上皮或基质细胞达到临界阈值时发生 累积的遗传突变事件，随着衰老而恢复为 胚胎克隆。 在雄激素和雌激素的允许作用下， 胚胎克隆通过异常分泌获得自主生长 肽生长因子。 肽生长因子直接介导 负责I期诱导的上皮和基质相互作用 和BPH结节的维护。 雄激素和雌激素可能会发挥 在II期中更重要的作用，BPH结节的扩散加速度 后来的生活。 该工作假设将在 黑猩猩，男人最接近的灵长类动物亲戚，共享98％的DNA序列 与人类的同源性，就像人一样，通过 以下特定目的：1）表征I期和II期 衰老的黑猩猩菌落的横截面分析自发BPH； 2）纵向表征I期和II期自发BPH 分析衰老的黑猩猩殖民地； 3）确定关系 通过实验性地到肽生长因子的雄激素和雌激素 通过荷尔蒙操纵在黑猩猩中诱导BPH。 假设 雄激素和雌激素是允许的，肽生长因子 直接负责异常上皮和基质 负责BPH的互动将在衰老的黑猩猩中测试 最小的侵入性生存方法。 更具体地说，两者都是 肽生长因子的时间和空间表达[转化 生长因子A（TGFA），转化生长因子B（TGFB）和基本 成纤维细胞生长因子（BFGF）]及其受体[表皮生长 因子受体（EGFR）和TGFB受体I型和II型（TGFB RI和II型） RII）]及其与雄激素（睾丸激素）和雌激素的关系 （雌二醇和雌激素）应提供有关病因的重要线索 和BPH的自然历史。 更重要的是，这些研究可能会拥有未来 通过作为确定自发BPH的基础来承诺 可以通过可预防或治疗性操纵来修改非人类灵长类动物 后来可以应用于人的BPH。