Development of Nonhuman Primate Models for PSA Biology Studies

简介（申请人提供）：常见的前列腺疾病包括前列腺癌、良性前列腺增生（BPH）和前列腺炎。这些疾病是造成大量死亡率和发病率的原因。前列腺特异性抗原（PSA）在这些疾病发展的早期以增高的水平释放到血液中，因此被广泛用于前列腺癌的筛查、诊断和监测。然而，由于PSA的敏感性和特异性较低，其作为前列腺疾病筛查的临床局限性。目前迫切需要了解血清PSA水平个体差异的原因。这项KO1提案的长期目标是为Mubiru博士准备一个独立的职业生涯，专注于开发用于PSA生物学研究的NHP模型和工具。Mubiru博士是一名受过双重训练的兽医/科学家，拥有兽医硕士、硕士和博士学位。他参与了转基因小鼠的开发以及前列腺癌生物标志物的鉴定。Mubiru博士将获得与前列腺疾病相关的分子和群体遗传学技能。遗传学家和基因组学专家J. Rogers博士将担任他的导师。UTHSCSA细胞与结构生物学教授Leach博士将担任联合导师。Mubiru博士将专门研究西南生物医学研究基金会（SFBR）维护的两种非人灵长类动物（狒狒和恒河猴）的前列腺。我们的假设是：1)非人类灵长类动物是研究PSA生物学的最佳动物模型；2)非人类灵长类动物的血清PSA水平是由遗传决定的；3)肥胖和肥胖相关因素影响血清PSA浓度。本课题的具体目的是：1)研究狒狒和恒河猴前列腺的解剖和组织学；2)研究年龄和遗传对这两个物种之间PSA变异的影响；3)鉴定PSA基因启动子区域和雄激素受体基因外显子1的DNA多态性，并评估这些多态性对血清PSA水平变异的影响。iv)研究肥胖及其相关表型与血清PSA水平之间的关系。本建议的目的将通过多学科方法和合作研究来解决。

DESCRIPTION (provided by applicant): Common prostatic diseases include prostate cancer, benign prostatic hyperplasia (BPH) and prostatitis. These diseases are a cause of significant mortality and morbidity. Prostate specific antigen (PSA) is released at increased levels into the blood early in the development of these diseases and therefore is widely used for screening, diagnosing and monitoring of prostate cancer. However, PSA has clinical limitations as a screen for prostatic diseases due to its low sensitivity and specificity. There is an urgent need for information about the causes of individual variation in serum PSA levels. The long term goal of this KO1 proposal is to prepare Dr. Mubiru for an independent career focused on the development of NHP models and tools for the study of PSA biology. Dr. Mubiru is a dual-trained veterinarian/scientist with DVM, MS and PhD degrees. He has been involved in the development of transgenic mice as well as in identifying biomarkers for prostate cancer. Dr Mubiru will acquire skills in molecular and population genetics as they relate to prostatic diseases. Dr. J. Rogers, a geneticist and genomics expert will serve as his mentor. Dr. Leach, a Professor in the Dept. of Cellular and Structural Biology at UTHSCSA will serve as co-mentor. Dr. Mubiru will specifically study the prostate of two nonhuman primate species (baboon, rhesus) maintained at the Southwest Foundation for Biomedical Research (SFBR). Our hypothesis is that 1) nonhuman primate species are the best animal models to study PSA biology, 2) serum PSA levels in nonhuman primates are genetically determined, 3) factors relating to adiposity and obesity affect serum PSA concentration. The specific aims of this proposal are i) study the anatomy and histology of the prostate of the baboon and rhesus, ii) investigate the influence of age and genetics on variation in PSA among these two species, iii) identify DNA polymorphisms in both the promoter regions of the PSA gene and exon 1 of the androgen receptor gene and assess the influence of these polymorphisms on variation in serum PSA levels, iv) investigate the relationship between obesity and its related phenotypes on one hand and serum PSA levels on the other. The aims of this proposal will be addressed using multidisciplinary approaches and through collaborative studies.