Alteration in the hypothalamic-pituitary-gonadal axis and frailty in aging men with HIV

人类免疫缺陷病毒（HIV）感染者（PWH）的数量正在增加， 虚弱的风险，这增加了与年龄相关的不良结局的风险，包括福尔斯、住院和 mortality.虚弱的机制尚未完全理解，特别是在PWH中。的目标 这项建议是研究游离睾酮和性激素结合球蛋白（SHBG） 浓度与HIV感染者的虚弱和炎症有关。我们假设免费 睾酮和SHBG是识别PWH的关键生物标志物， 从合成代谢药物的干预中获益。我们的具体目标是：1）确定 循环游离睾酮和SHBG与事件虚弱使用国家的最先进的激素测量之间 男性HIV感染者，2）确定男性游离睾酮昼夜变化与HIV血清状态的关系 及其与全身性炎症的关系，3）确定新型SHBG聚糖与虚弱的关系 艾滋病毒感染者中。 在目标1中，我们将用最先进的方法测量血清游离睾酮和HIV感染男性的SHBG 多中心艾滋病队列研究（MACS）是一项自1984年以来正在进行的前瞻性研究， 同性恋和双性恋男性HIV-1感染的自然史和治疗史。康贝特人将以 自2007年以来，在每半年一次的访问中收集这些激素与脆弱事件的关联。 在目标2中，我们将选择在上午和下午采集血液样本的感染和不感染艾滋病毒的男性进行评估。 游离睾酮和全身炎症[白细胞介素6（IL 6）和可溶性TNF-α]的昼夜变化 受体II（sTNFRII）]。 在目标3中，我们将研究HIV感染者的新型SHBG糖型，SHBG的鉴定和定量 将通过毛细管电泳和凝集素微阵列进行糖型分析。拟议的研究旨在 为游离睾酮和SHBG在虚弱中的作用及其与全身性疾病的关系提供了新的见解。 炎症获奖期间的目标包括获得生物统计方法方面的先进专业知识， 设计和进行流行病学研究，以及在糖型测量方面的实践经验 从血浆蛋白和糖组学数据的解释，通过指导研究，量身定制的教学 课程作业，并监督相关实验室技术的性能。长期目标包括发展 职业生涯作为一个独立的调查员在转化流行病学和开发新的方法来治疗 以及预防与年龄有关的结果，例如威尔斯亲王医院的虚弱。

PROJECT SUMMARY/ABSTRACT People with human immunodeficiency virus (HIV), (PWH), are at increased risk of frailty, which increases the risk of adverse age-related outcomes, including falls, hospitalization and mortality. The mechanisms of frailty are not completely understood, particularly among PWH. The objectives of this proposal are to study the extent to which free testosterone and sex hormone binging globulin (SHBG) concentrations are associated with frailty and inflammation in men with HIV. We hypothesize that free testosterone and SHBG are key biomarkers for identifying PWH at the highest risk of frailty and who may benefit from intervention with anabolic agents. Our specific aims are to: 1) Determine the association of circulating free testosterone and SHBG with incident frailty using state-of-the-art hormone measurements among men with HIV, 2) Determine the association of diurnal variation in free testosterone with HIV serostatus in men and its association with systemic inflammation, 3) Determine the association of novel SHBG glycans with frailty among men with HIV. In Aim 1, we will measure serum free testosterone with state-of-the-art methods and SHBG in men with HIV who are part of the Multicenter AIDS Cohort Study (MACS), an ongoing prospective study since 1984 studying the natural and treated histories of HIV-1 infection in homosexual and bisexual men. We will determine the associations of these hormones with incident frailty, collected at semi-annual visits since 2007. In Aim 2, we will select men with and without HIV that have collected blood samples in AM and PM to assess diurnal variation in free testosterone and systemic inflammation [Interleukin 6 (IL6) and soluble TNF-alpha receptors II (sTNFRII)]. In Aim 3, we will study novel SHBG glycoforms in men with HIV, the identification and quantification of SHBG glycoforms will be performed by capillary electrophoresis and lectin microarray. The proposed research aims to provide new insights to the contribution of free testosterone and SHBG in frailty and its relationship with systemic inflammation. The goals during the award period include gaining advanced expertise in biostatistical methods, design and conduct epidemiological studies, as well as hands-on experience in the measurement of glycoforms from plasma proteins and interpretation of glycomic data through mentored research, tailored didactic coursework, and supervised performance of relevant laboratory techniques. Long-term goals include developing a career as an independent investigator in translational epidemiology and developing new approaches to treating and preventing age-related outcomes such as frailty in PWH.