A DIAGNOSTIC TEST TO ASSESS RISK ASSOCIATED WITH ANDROGEN THERAPY

描述（由申请人提供）：雄激素治疗的适应症已经扩大，因此，今天，雄激素用于男性和女性，除了用于治疗原发性（或继发性）性腺功能减退症外，还具有增加骨矿物质密度、诱导更大的肌肉质量和力量、增强性功能和改善情绪的潜在益处。雄激素也被认为是治疗类风湿性关节炎、伤口愈合和男性避孕的药物。2002年，美国有超过170万张睾丸激素处方，比2001年增加了30%，比1999年增加了170%。此外，Frost & Sullivan报告称，雄激素市场正以25%的复合年增长率（CAGR）增长。与该建议特别相关的是，应该注意的是，尽管老龄化人口显然是雄激素治疗可能适用的重要人口统计学，但该相同人口也处于中风或发展诸如阿尔茨海默病的神经退行性疾病的较高风险中。鉴于文献中关于雄激素是否有益或有害的报告之间存在差异，迫切需要设计一种有效的筛查工具，以更好地定义最有可能从雄激素治疗中获益的人群。目前尚无已知的诊断方法来确定考虑接受雄激素治疗的患者的风险。因此，该I期申请概述了一种基于我们的初步数据的策略，以开发用于相对评估两种不同雄激素受体的诊断工具，每种雄激素受体似乎都介导对细胞存活的不同影响。一种受体（经典的细胞内/核雄激素受体）有助于有益的（细胞存活促进）作用，而另一种膜雄激素受体（mAR）促进细胞死亡。这种潜在的“竞争”机制可以解释文献中关于雄激素是保护性的还是促进细胞功能障碍和死亡的差异。重要的是，这些数据作为我们假设的基础，该假设指出，这两种竞争受体机制的相对丰度（或比率）预测个体是否会对雄激素产生有利的反应或更容易产生雄激素的负面影响。这一假设将在两个具体目标的范围内进行检验。第一个项目将开发和验证一种方法，以同时评估脑组织和血液（白色血细胞）中经典AR和mAR的水平。后者将解决这些受体的简单血液测量是否可以可靠地预测雄激素靶组织中的mAR：AR比率。第二个目的是通过评估卒中动物模型中与雄激素相关的阴性结果是否与受累脑区和白色血细胞（后者作为脑的替代标志物）中相对较高的mAR丰度相关，来测试mAR：AR比对雄激素治疗结果的可预测性。该项目的成功完成将为II期STTR应用和诊断工具的开发提供必要的基础，以确定雄激素治疗不仅适用于哪些个体，而且有效和安全。

DESCRIPTION (provided by applicant): The indications for androgen therapy has expanded such that today, androgens are used in both men and women, and in addition to their use in treating primary (or secondary) hypogonadism the potential benefit of increasing bone mineral density, inducing greater muscle mass and strength, enhancing sexual function, and improving mood. Androgens are also being considered as a treatment for rheumatoid arthritis, wound healing, and male contraception. More than 1.7 million prescriptions for testosterone were written in the United States in 2002, representing a 30% increase over that prescribed in 2001 and a 170% increase from that prescribed in 1999. Further, Frost & Sullivan report that that the market for androgens is growing at a 25% compound annual growth rate (CAGR). Of specific relevance to this proposal, it should be noted that though the aging population is clearly an important demographic for which androgen therapy may be indicated, this same population is also at a higher risk for stroke or developing such neurodegenerative diseases as Alzheimer's disease. Given the discrepancy between reports in the literature as to whether androgens are beneficial or detrimental, there is a critical need to devise an effective screening tool to better define the population most likely to benefit from androgen therapy. Currently there is no known diagnostic available to define risk in a patient who is considered for androgen therapy. As such, this Phase I application outlines a strategy, based on our preliminary data, to develop a diagnostic tool for the relative assessment of two pharmacologically distinct androgen receptors, each of which appear to mediate different effects on cell survival. One receptor (the classical, intracellular/nuclear androgen receptor), subserves a beneficial (cell survival promoting) effect, while the other, a membrane androgen receptor (mAR), promotes cell death. Such potentially "competing" mechanisms could explain the discrepancy in the literature as to whether androgens are protective or promote cell dysfunction and death. Importantly, these data serve as the basis for our hypothesis, which states that the relative abundance (or ratio) of these two competing receptor mechanisms predicts whether individuals will respond favorably to androgens or are more prone to the negative consequences of androgens. This hypothesis will be tested within the confines of two specific aims. The first will develop and validate a methodology to simultaneously assess the levels of the classical AR and the mAR from both brain tissue and blood (white blood cells). The latter will address whether simple blood measurements of these receptors may reliably predict the mAR:AR ratio in androgen's target tissue. The second aim will test the predictability of the mAR:AR ratio on the therapeutic outcome of androgens by assessing if the negative outcome associated with androgens in an animal model of stroke is correlated with a relatively higher abundance of mAR in both the affected brain regions and in white blood cells (the latter serving as a surrogate marker for the brain). Successful completion of this project will provide the necessary foundation for a Phase II STTR application and the development of a diagnostic tool to define those individuals for whom androgen therapy is not only indicated, but also effective and safe.