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

感染艾滋病毒的老年男性下丘脑-垂体-性腺轴的改变和虚弱

• 批准号: 10545981
• 负责人: Jenny Pena Dias
• 金额: $ 13.01万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10545981
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Aging; Anabolic Agents; Apnea; Award; Biological Markers; Biostatistical Methods; Bisexual; Blood specimen; Capillary Electrophoresis; Carrier Proteins; Characteristics; Chronic; Clinical; Data; Disease; Diurnal Rhythm; Elderly; Enrollment; Epidemic; Epidemiology; Free Association; Functional disorder; General Population; Globulins; Glycoproteins; Goals; Gonadal Steroid Hormones; HIV; HIV Seronegativity; HIV Seropositivity; HIV-1; Homosexuals; Hormones; Hospitalization; Hypogonadism; Hypothalamic dysfunction; Hypothalamic structure; IL6 gene; Immune; Immunoglobulin G; Impairment; Infection; Inflammation; Inflammatory; Interleukin-6; Intervention; Investigation; Knowledge; Laboratories; Lectin; Longevity; Longitudinal Studies; Measurement; Measures; Mediating; Mentors; Methods; Monosaccharides; Outcome; Pathogenesis; Pattern; Performance; Persons; Physical Function; Pituitary Gland; Plasma; Plasma Proteins; Play; Polysaccharides; Prevalence; Prospective Studies; Proteins; Recording of previous events; Reporting; Research; Research Personnel; Risk; Role; Serum; Sex Hormone-Binding Globulin; Sleep; Statistical Methods; Supervision; Systemic infection; TNF gene; Techniques; Testosterone; The Multicenter AIDS Cohort Study; Time; Visit; Work; age related; antiretroviral therapy; bone strength; career; comorbidity; design; epidemiology study; experience; falls; frailty; glycosylation; high risk; hypothalamic pituitary gonadal axis; inflammatory marker; inflammatory milieu; insight; men; mortality; new therapeutic target; novel; novel strategies; patient population; premature; prevent; receptor; systemic inflammatory response

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.

项目摘要/摘要人类免疫缺陷病毒(HIV)携带者(PWH)人数增加 虚弱的风险，这增加了与年龄相关的不良结局的风险，包括跌倒、住院和 死亡率。脆弱的机制还不完全清楚，特别是在PWH中。的目标 这项建议是为了研究游离睾丸素和性激素结合球蛋白(SHBG)的程度 浓度与艾滋病毒携带者的虚弱和炎症有关。我们假设是免费的 睾酮和SHBG是识别PWH脆弱风险最高的关键生物标志物，谁可能 从合成代谢制剂的干预中受益。我们的具体目标是：1)确定 使用最先进的激素测量方法测量循环中的游离睾酮和SHBG与发病易感性 男性HIV感染者，2)确定男性体内游离睾酮的昼夜变化与HIV血清状态的关系 及其与全身炎症的关系，3)确定新的SHBG多糖与脆性的关联 在感染艾滋病毒的男性中。 在目标1中，我们将用最先进的方法测量艾滋病毒男性患者的血清游离睾酮和SHBG 他们是多中心艾滋病队列研究(MACS)的一部分，这是一项自1984年以来正在进行的前瞻性研究，研究 同性恋者和双性恋者感染HIV-1的自然和治疗历史。我们将确定 这些激素与事件脆弱性的关系，自2007年以来每半年一次的访问中收集。 在目标2中，我们将选择在上午和下午采集血液样本的艾滋病毒携带者和非艾滋病毒携带者进行评估 游离睾酮与全身炎症[白介素6和可溶性肿瘤坏死因子-α]的昼夜变化 受体II(STNFRII)]。 在目标3中，我们将研究艾滋病毒男性中新的SHBG糖形式，SHBG的鉴定和定量 糖型将通过毛细管电泳法和凝集素芯片进行分析。这项拟议的研究旨在 对游离睾酮和SHBG在虚弱中的贡献及其与系统性疾病的关系提供新的见解 发炎。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，以及在糖形式测量方面的实践经验 从血浆蛋白质和血糖数据的解释通过指导研究，量身定做的教学 课程作业，以及相关实验室技术的监督执行。长期目标包括发展 在翻译流行病学和开发新的治疗方法方面的独立调查者的职业生涯 以及预防与年龄相关的结果，如PWH中的虚弱。