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: 10681377
• 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/10681377
• 关键词: Acceleration; Acquired Immunodeficiency Syndrome; Affect; Age; Aging; Anabolic Agents; Apnea; Award; Biological Markers; Biostatistical Methods; Bisexual; Blood specimen; Capillary Electrophoresis; Carrier Proteins; Characteristics; Chronic; Clinical; Communicable Diseases; 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; Immune; Immunoglobulin G; Impairment; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Intervention; Investigation; Knowledge; Knowledge acquisition; 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; Process; Prospective Studies; Protein Glycosylation; Proteins; Recording of previous events; Reporting; Research; Research Personnel; Risk; Role; Serum; Sex Hormone-Binding Globulin; Sleep; Statistical Methods; Systemic infection; TNFRSF1A 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; improved; inflammatory marker; inflammatory milieu; inflammatory modulation; insight; men; mortality; new therapeutic target; novel; novel strategies; patient population; premature; prevent; sialylation; 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.

人类免疫缺陷病毒（HIV），（PWH）的项目摘要/抽象人员正在增加 脆弱的风险，增加了与年龄相关的不良后果的风险，包括跌倒，住院和 死亡。脆弱的机制尚未完全理解，尤其是在PWH中。目标的目标 该建议是研究自由睾丸激素和性激素弯曲球蛋白（SHBG）的程度 浓度与艾滋病毒男性的脆弱和炎症有关。我们假设这是免费的 睾丸激素和SHBG是识别PWH具有最高风险的PWH的关键生物标志物，谁可以 受益于合成代谢剂的干预。我们的具体目的是：1）确定 使用最先进的激素测量结果循环免费的睾丸激素和SHBG，并具有事件脆弱 艾滋病毒的男性，2）确定自由睾丸激素中昼夜变异与男性HIV血清的缔合 及其与系统性炎症的关联，3）确定新型SHBG聚糖与脆弱的关联 在艾滋病毒的男性中。 在AIM 1中，我们将使用最先进的方法测量无血清睾丸激素，而HIV男性的SHBG 谁是多中心艾滋病队列研究（MAC）的一部分，这是自1984年以来正在进行的前瞻性研究 同性恋和双性恋男性中HIV-1感染的自然和处理的历史。我们将确定 自2007年以来，这些激素与事件脆弱的关联是在半年度访问时收集的。 在AIM 2中，我们将选择在AM和PM中收集血液样本的患有和没有HIV的男性以评估 游离睾丸激素和全身性炎症的昼夜变化[白介素6（IL6）和可溶性TNF-alpha 受体II（stnfrii）]。 在AIM 3中，我们将研究HIV男性的新型SHBG糖型，SHBG的识别和定量 糖型将通过毛细血管电泳和凝集素微阵列进行。拟议的研究旨在 为脆弱的自由睾丸激素和SHBG的贡献提供新的见解及其与系统的关系 炎。奖励期内的目标包括获得生物统计学方法的高级专业知识， 设计和进行流行病学研究，以及测量糖型的动手经验 从血浆蛋白和通过指导研究对血糖数据的解释，量身定制的DIDACTIC 课程工作以及相关实验室技术的监督性能。长期目标包括发展 从事转化流行病学独立研究者的职业，并开发了治疗的新方法 并防止与年龄有关的结果，例如PWH中的脆弱性。