DEVELOPMENT OF THE CYNOMOLGUS MONKEY AS A MODEL FOR PSA BIOLOGY STUDIES

食蟹猴作为 PSA 生物学研究模型的开发

• 批准号: 8357691
• 负责人: James Nkambwe Mubiru
• 金额: $ 3.36万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357691
• 关键词: Address; American; Biological Markers; Biology; Blood; Cells; Cessation of life; Characteristics; Clinical; Coagulation Process; Data; Development; Diagnosis; Diet; Disease; Documentation; Ejaculation; Exhibits; Fatty acid glycerol esters; Funding; Genetic; Gleason Grade for Prostate Cancer; Goals; Grant; Incidence; Individual; Macaca fascicularis; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Modeling; Monitor; National Center for Research Resources; Neoplasm Metastasis; Obesity; Outcome; Overweight; Pilot Projects; Primates; Principal Investigator; Process; Production; Prostate; Prostate-Specific Antigen; Prostatic Diseases; Reporting; Research; Research Infrastructure; Resources; Risk; Screening for Prostate Cancer; Screening procedure; Seminal Plasma; Sensitivity and Specificity; Serum; Source; Stream; Study models; Testing; Time; Uncertainty; United States National Institutes of Health; Variant; Weight; cancer cell; cancer risk; cost; feeding; men; mortality; nonhuman primate; novel; sugar

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The purpose of the study is to investigate the effect of feeding a high fat, high sugar diet on serum prostate specific antigen (PSA) in cynomolgus monkeys. Thirty cynomolgus monkeys will be fed a high fat, high sugar diet for 12 months. Prostate cancer is the most common non-cutaneous cancer in American men. It is estimated that more than 234,000 cases are diagnosed annually resulting in 27,000 deaths. A major characteristic of normal prostate cells and prostate cancer cells is selective production of PSA. The main function of PSA is to liquefy the seminal plasma clot after ejaculation. Normally PSA is restricted to the prostate gland and its secretions and very little is present in the blood stream. However, PSA is released at increased levels into the blood early in the development of prostatic diseases and therefore is widely used for screening, diagnosing and monitoring of prostate cancer, although it is also elevated in other disorders. Serum PSA level is the most widely used clinical biomarker for any cancer with about 45 million serum PSA tests performed per year worldwide. The use of PSA screening has resulted in a decline in both prostate cancer mortality and the incidence of metastases at the time of diagnosis. However, PSA has clinically meaningful limitations as a screen for prostate cancer due to its low sensitivity and specificity. Only 25-30% of men with elevated PSA ( 4ng/¿l) actually have cancer, and in addition, some men with cancer do not show elevated PSA. Added to this complexity is the finding that overweight men tend to exhibit lower PSA values than men of normal weight. The reason for this reduction in PSA with obesity is not understood, but the result is that overweight men have higher mortality due to prostate cancer, higher Gleason scores at diagnosis and respond to treatment poorly. The uncertainty in the interpretation of serum PSA levels is a major clinical concern. There is significant need for more information on the causes of individual variation in PSA levels among men at risk for prostate cancer. There is also a need to understand PSA biology as it may be more than a marker for prostate cancer but may actually be important in the disease process. The long-term goal of this line of research is to develop a nonhuman primate model for the study of the biology of PSA, and to use that model to investigate the various causes of individual variation in serum PSA levels that are not due to cancer itself. The known (non-cancer) causes of variation in serum levels of PSA include genetic differences among men, obesity, and possibly diet separate from obesity. In order to pursue larger external funding for analyses of the relationships among diet, obesity, adiposity and serum PSA in an appropriate nonhuman primate model, we need adequate preliminary data demonstrating that 1) we can reliably measure serum PSA in a given species, 2) the serum PSA levels in that species are negatively correlated with obesity, adiposity or BMI, and 3) we can manipulate diet and adiposity in order to experimentally control these variables and thus investigate the mechanisms through which diet or obesity influence PSA. The outcome of this pilot study will be novel information on the effect of this diet on serum PSA levels in cynomolgus monkeys. Documentation of this relationship will allow us to propose larger more detailed studies of the effect of diet, adiposity, obesity on serum PSA in nonhuman primates. This pilot study will specifically address the issue of why PSA levels are lower in obese individuals yet it has been reported that prostate cancer risk is increased with obesity. The results from this project will give answers to the current dilemma in the prostate cancer field that indicates that obese men have low serum PSA despite having higher prostate cancer mortality rates.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 本研究旨在探讨高脂高糖饮食对食蟹猴血清前列腺特异性抗原(PSA)的影响。30只食蟹猴将被喂以高脂肪、高糖饮食12个月。前列腺癌是美国男性最常见的非皮肤癌。据估计，每年诊断的病例超过234,000例，造成27,000人死亡。正常前列腺细胞和前列腺癌细胞的一个主要特征是选择性地产生PSA。PSA的主要功能是液化射精后的精浆凝块。正常情况下，PSA仅限于前列腺癌及其分泌物，血液中几乎没有PSA。然而，在前列腺疾病发展的早期，PSA被释放到血液中的水平增加，因此被广泛用于前列腺癌的筛查、诊断和监测，尽管它在其他疾病中也会升高。血清PSA水平是任何癌症最广泛使用的临床生物标记物，全球每年约有4500万次血清PSA检测。前列腺癌筛查的使用降低了前列腺癌的死亡率和确诊时的转移率。然而，PSA作为前列腺癌筛查的敏感性和特异性较低，在临床上有一定的局限性。在PSA升高(4 ng/L)的男性中，只有25%-30%的人实际患有癌症，此外，一些癌症患者没有表现出PSA升高。更复杂的是，发现超重男性往往比正常体重的男性表现出更低的PSA值。肥胖导致PSA下降的原因尚不清楚，但结果是超重男性因前列腺癌死亡率较高，确诊时格里森评分较高，对治疗的反应较差。对血清PSA水平的解释的不确定性是一个主要的临床问题。有必要更多地了解前列腺癌高危人群中PSA水平个体差异的原因。还有必要了解PSA生物学，因为它可能不仅仅是前列腺癌的标志，但实际上在疾病过程中可能是重要的。 这一系列研究的长期目标是开发一种非人类灵长类动物模型来研究PSA的生物学，并使用该模型来调查血清PSA水平的个体差异的各种原因，这些差异不是由于癌症本身造成的。已知的(非癌症)导致血清PSA水平变化的原因包括男性之间的遗传差异、肥胖，以及可能的饮食与肥胖分开。为了在合适的非人灵长类动物模型中寻求更多的外部资金来分析饮食、肥胖、肥胖和血清PSA之间的关系，我们需要足够的初步数据来证明：1)我们可以可靠地测量特定物种的血清PSA，2)该物种的血清PSA水平与肥胖、肥胖或BMI呈负相关，以及3)我们可以通过操纵饮食和肥胖来控制这些变量，从而研究饮食或肥胖影响PSA的机制。这项初步研究的结果将是关于这种饮食对食蟹猴血清PSA水平影响的新信息。这种关系的记录将使我们能够提出更大、更详细的研究，研究饮食、肥胖和肥胖对非人类灵长类动物血清PSA的影响。这项初步研究将专门解决为什么肥胖者的PSA水平较低的问题，但有报道称，前列腺癌的风险随着肥胖而增加。该项目的结果将为前列腺癌领域目前的困境提供答案，这表明肥胖男性尽管前列腺癌死亡率较高，但血清PSA水平较低。