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.

项目摘要/摘要 人类免疫缺陷病毒 (HIV) 感染者 (PWH) 的患病率增加 虚弱的风险，这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。虚弱的机制尚不完全清楚，特别是对于感染者来说。的目标 该提案旨在研究游离睾酮和性激素结合球蛋白 (SHBG) 的程度 浓度与艾滋病毒感染者的虚弱和炎症有关。我们假设免费 睾酮和性激素结合球蛋白 (SHBG) 是识别 PWH 虚弱风险最高以及哪些人群可能的关键生物标志物 受益于合成代谢药物的干预。我们的具体目标是： 1) 确定关联 使用最先进的激素测量方法对患有意外衰弱的循环游离睾酮和性激素结合球蛋白 男性 HIV 感染者，2) 确定男性游离睾酮的昼夜变化与 HIV 血清状态的关联 及其与全身炎症的关联，3) 确定新型 SHBG 聚糖与虚弱的关联 感染艾滋病毒的男性中。 在目标 1 中，我们将采用最先进的方法测量 HIV 感染者的血清游离睾酮和性激素结合球蛋白 (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 年以来持续进行的前瞻性研究 同性恋和双性恋男性的 HIV-1 感染自然史和治疗史。我们将确定 自 2007 年以来每半年访视收集一次这些激素与突发性衰弱的关联。 在目标 2 中，我们将选择在上午和下午采集了血液样本的感染和未感染 HIV 的男性进行评估 游离睾酮和全身炎症 [白细胞介素 6 (IL6) 和可溶性 TNF-α] 的昼夜变化 受体 II (sTNFRII)]。 在目标 3 中，我们将研究男性 HIV 感染者中新型 SHBG 糖型，以及 SHBG 的鉴定和定量 糖型将通过毛细管电泳和凝集素微阵列进行。拟议的研究旨在 为游离睾酮和性激素结合球蛋白 (SHBG) 在衰弱中的作用及其与全身系统的关系提供新的见解 炎。奖励期间的目标包括获得生物统计方法的高级专业知识， 设计和进行流行病学研究，以及糖型测量的实践经验 通过指导研究、量身定制的教学，从血浆蛋白和糖组数据的解释 课程作业，并监督相关实验室技术的执行。长期目标包括发展 作为转化流行病学的独立研究者并开发新的治疗方法 预防与年龄相关的后果，例如感染者虚弱。