Soluble Insulin Receptor Dysfunction Correlates with HAND in HIV+ women on CART

可溶性胰岛素受体功能障碍与接受 CART 治疗的 HIV 女性中的 HAND 相关

• 批准号: 8208259
• 负责人: VALERIE WOJNA
• 金额: $ 25.6万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208259
• 关键词: Alternative Splicing; Anti-Retroviral Agents; Biological Markers; Blood; Blood Glucose; Cells; Cross-Sectional Studies; DNA Sequence; Data; Development; Diagnosis; Disease; Early Diagnosis; Early treatment; Functional disorder; Glycosylated Hemoglobin; Goals; HIV; HIV Infections; Homeostasis; Individual; Insulin Receptor; Insulin Resistance; Length; Leukocytes; Mammalian Cell; Measures; Messenger RNA; Metabolic; Metabolism; Modality; Modeling; Monitor; Neurocognitive; OGTT; Outcome; Patients; Plasma; Prevalence; Price; Procedures; Process; RNA Splicing; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; Severities; Testing; Transcript; Transmembrane Domain; Variant; Woman; cohort; disorder control; novel; receptor; treatment effect; treatment response

DESCRIPTION (provided by applicant): The prevalence of HIV-associated neurocognitive disorders (HAND) has increased owing to the widespread use of combined antiretroviral treatment (CART) and resulting longer survival of HIV-infected patients. Among HIV-seropositive patients on CART, most suffer from the milder forms of HAND. Despite the increased prevalence of HAND, we lack good biomarkers for the disease (Price, 2010). Recently, blood sugar metabolism abnormalities have been identified in HIV-infected individuals and associated with HAND. In addition, retrospective data from our own cohort of HIV-seropositive women on CART show that high plasma soluble insulin receptor (sIR) full-length levels are associated with the presence and severity of HAND. Our long-term goal is to identify a biomarker for HAND. The rationale for the current study lies with previous observations by our lab and others that blood sugar metabolism abnormalities are associated with HAND. Our central hypothesis is that these abnormalities contribute to the development and progression of HAND. The objective of the present study is to determine if changes in plasma sIR full-length levels are associated with milder forms of HAND in a cohort of HIV-seropositive women using CART. We propose 3 aims: 1. To determine if sIR ectodomain (1) and full-length (12) subunits are increased in HIV-infection in a cohort of HIV- seropositive women using CART, 2. To determine if high plasma sIR full-length levels are associated with HAND, and 3. To determine if alternative splicing of the insulin receptor mRNA transcript correlates with plasma sIR full-length levels in HIV-seropositive women with HAND. We expect to find an association between plasma sIR full-length and HAND, and increased sIR full-length to be associated with increased alternative splicing of IR mRNA. This study is novel in testing the possibility that plasma sIR full-length could serve as a blood biomarker for presence and severity of HAND. It is significant since sIR full-length could assist in early diagnosis and monitoring treatment responses, as well as in understanding the pathogenic processes of HAND. PUBLIC HEALTH RELEVANCE: We found that plasma soluble insulin receptor levels are associated with the presence and severity of HIV- associated neurocognitive disorders (HAND) in HIV-seropositive women on combined antiretroviral treatment (CART). We propose to further evaluate this association and explore its underlying mechanisms. If our findings are positive, we will have identified a blood biomarker for the early diagnosis and treatment of HAND in HIV- seropositive women on CART.

描述（由申请人提供）：由于联合抗逆转录病毒治疗（CART）的广泛使用以及导致艾滋病毒感染者的生存期延长，艾滋病毒相关神经认知障碍（HAND）的患病率有所增加。在接受 CART 治疗的 HIV 血清阳性患者中，大多数患有较轻度的 HAND。尽管 HAND 患病率有所增加，但我们缺乏该疾病的良好生物标志物（Price，2010）。最近，在 HIV 感染者中发现血糖代谢异常并与 HAND 相关。此外，我们自己的 CART 治疗中 HIV 血清阳性女性队列的回顾性数据表明，高血浆可溶性胰岛素受体 (sIR) 全长水平与 HAND 的存在和严重程度相关。我们的长期目标是确定 HAND 的生物标志物。当前研究的基本原理在于我们实验室和其他实验室之前的观察结果，即血糖代谢异常与 HAND 有关。我们的中心假设是这些异常有助于 HAND 的发生和进展。本研究的目的是确定血浆 sIR 全长水平的变化是否与使用 CART 的 HIV 血清阳性女性队列中较轻的 HAND 形式相关。我们提出了 3 个目标：1. 确定使用 CART 的 HIV 血清阳性女性队列中 sIR 胞外域 (1) 和全长 (12) 亚基是否在 HIV 感染中增加，2. 确定高血浆 sIR 全长水平是否与 HAND 相关，以及 3. 确定胰岛素受体 mRNA 转录本的选择性剪接是否与 HIV 血清阳性女性血浆 sIR 全长水平相关 用手。我们期望发现血浆 sIR 全长和 HAND 之间的关联，并且 sIR 全长的增加与 IR mRNA 选择性剪接的增加相关。这项研究的新颖之处在于测试了血浆 sIR 全长可以作为 HAND 存在和严重程度的血液生物标志物的可能性。这很重要，因为全长 sIR 可以帮助早期诊断和监测治疗反应，以及了解 HAND 的致病过程。 公共健康相关性：我们发现，在接受联合抗逆转录病毒治疗 (CART) 的 HIV 血清阳性女性中，血浆可溶性胰岛素受体水平与 HIV 相关神经认知障碍 (HAND) 的存在和严重程度相关。我们建议进一步评估这种关联并探索其潜在机制。如果我们的研究结果是积极的，我们将确定一种血液生物标志物，用于 CART 上 HIV 血清阳性女性的 HAND 早期诊断和治疗。