Interactions of Alcohol and Pain in the Context of HIV

艾滋病毒背景下酒精和疼痛的相互作用

• 批准号: 10762596
• 负责人: Taylor Fitzpatrick-Schmidt
• 金额: $ 4.69万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10762596
• 关键词: ARHGEF5 gene; Acute; Affect; Alcohol consumption; Alcohol dependence; Alcohols; Analgesics; Animal Model; Animals; Area; Behavior; Brain; Chronic; Chronic Disease; Clinical; Data; Development; Disease Progression; Emotions; Ensure; Ethanol; Exposure to; Fellowship; Future; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Glycoproteins; HIV; HIV envelope protein; HIV neuropathy; HIV/AIDS; Heavy Drinking; Hormones; Hydrocortisone; Hyperalgesia; Inflammation; Investigation; Link; Literature; Measures; Mechanics; Mediating; Medicine; Mentors; Methods; Mifepristone; Modeling; Molecular; National Research Service Awards; Nerve; Nervous System; Neurology; Neuronal Plasticity; Neurons; Neuropathy; Nociception; Pain; Pathogenesis; Patient Self-Report; Pattern; Peripheral; Peripheral Nerves; Persons; Phosphorylation; Physicians; Play; Population; Pre-Clinical Model; Prevalence; Property; Rattus; Receptor Signaling; Recording of previous events; Reporting; Research; Rodent Model; Role; Scientist; Self Administration; Self Medication; Signal Transduction; Stress; Symptoms; Techniques; Testing; Toxic effect; Training; United States National Institutes of Health; Viral Proteins; Western Blotting; Work; alcohol effect; alcohol exposure; alcohol research; alcohol risk; alcohol use disorder; antagonist; career; career development; chronic pain; cingulate cortex; cohort; comorbidity; disorder risk; drinking; high risk drinking; hormonal signals; hydrocortisone receptor; insight; negative affect; negative emotional state; pain sensitivity; pain symptom; painful neuropathy; perineural; phosphatidylethanol; pre-clinical; sensory neuropathy; stem; training opportunity; translational physician; translational study; translational therapeutics; vapor

Abstract This NRSA F30 fellowship will prepare the applicant for a successful career as a translational physician- scientist. Career development training will focus on High Priority HIV/AIDS comorbidity-related research, utilizing a preclinical rodent model of HIV gp120-induced neuropathic pain alongside investigation of a clinical population of people living with HIV (PLWH). Alcohol use disorder (AUD) is a chronic disease associated with excessive drinking and is frequently comorbid in people living with HIV (PLWH). AUD often results in the emergence of negative emotional states that influence the desire to consume alcohol, and one potentially important contributor to these negative affective states in PLWH is HIV-associated painful neuropathies (HIV- N). Thus, the rationale for drinking in PLWH may stem from a desire for self-medication of pain due to the analgesic properties of alcohol. Importantly, excessive alcohol use can also result in hyperalgesia, a condition that may be worsened by HIV-N. Previous work has described the emergence of hyperalgesia in animals made dependent on alcohol. Preliminary investigation in a cohort of PLWH has also revealed positive associations between AUDIT (Alcohol Use Disorders Identification Test) scores and circulating levels of the stress hormone cortisol. At the molecular level, the transcriptional activity of glucocorticoid receptors (GRs) is directly controlled via phosphorylation status. Dysregulation of GR signaling may facilitate the transition to AUD and contribute to AUD-associated hyperalgesia, potentially playing a role in development of HIV-N. Furthermore, chronic pain can result in supraspinal plasticity in brain areas linking nociception and negative emotion, such as the cingulate cortex, which may also contribute to the establishment or progression of AUD. In support of this, preliminary data has discovered increases in GR phosphorylation in the cingulate of alcohol-dependent rats. To study the contributions of alcohol and HIV to HIV-N, we’ve utilized an established preclinical rodent model employing perineural exposure to the HIV envelope protein, glycoprotein 120 (gp120), which is closely involved in the pathogenesis of HIV-N. Taken together, our preliminary data and the existing literature support the hypothesis that increased pain associated with HIV and at-risk alcohol use is driven by heightened glucocorticoid receptor (GR) activity. The proposed study will employ a wide array of techniques to test two hypotheses: (1) GR activity mediates hyperalgesia associated with HIV gp120 and alcohol dependence in rats and (2) circulating cortisol levels are associated with pain symptoms and AUD risk measures in PLWH. Findings from this study will advance our understanding of the role of stress hormone signaling in the interplay between HIV- and alcohol-associated pain. With the support of a strong mentoring team and the NIH P60 Comprehensive Alcohol-HIV/AIDS Research Center (CARC), completion of the proposed research and training plan will ensure that the applicant is prepared for an impactful career in academic medicine.

抽象的 NRSA F30 奖学金将为申请人作为转化医师的成功职业生涯做好准备- 科学家的职业发展培训将重点关注与艾滋病毒/艾滋病合并症相关的高优先级研究， 利用 HIV gp120 诱导的神经性疼痛的临床前啮齿动物模型以及临床研究 艾滋病毒感染者 (PLWH) 是一种与酒精使用障碍相关的慢性疾病。 过量饮酒且艾滋病毒感染者 (PLWH) 中经常出现共病，通常会导致艾滋病毒感染者 (PLWH)。 影响饮酒欲望的负面情绪状态的出现，以及一种潜在的 艾滋病病毒相关的疼痛性神经病（HIV- N) 因此，感染者饮酒的理由可能源于自我治疗疼痛的愿望。 酒精的镇痛作用重要的是，过量饮酒也会导致痛觉过敏。 HIV-N 可能会加剧这种情况，之前的研究已经描述了动物中痛觉过敏的出现。 对一组感染者的初步调查也显示出积极的关联。 AUDIT（酒精使用障碍识别测试）分数与压力荷尔蒙循环水平之间的关系 在分子水平上，糖皮质激素受体（GR）的转录活性受到直接控制。 通过 GR 信号传导失调可能会促进向 AUD 的转变并有助于 AUD 相关的痛觉过敏，可能在 HIV-N 的发展中发挥作用，此外，慢性疼痛。 可以导致连接伤害感受和负面情绪的大脑区域出现脊髓上可塑性，例如 扣带皮层，这也可能有助于 AUD 的建立或进展。 初步数据发现酒精依赖大鼠的扣带回 GR 磷酸化增加。 为了研究酒精和 HIV 对 HIV-N 的影响，我们利用了已建立的临床前啮齿动物模型 采用神经周围暴露于 HIV 包膜蛋白、糖蛋白 120 (gp120)，该蛋白与 HIV 包膜蛋白密切相关 综上所述，我们的初步数据和现有文献支持了 HIV-N 的发病机制。 假设与艾滋病毒和高危饮酒相关的疼痛增加是由患者引起的 拟议的研究将采用多种技术来测试两种糖皮质激素受体（GR）活性。 假设：(1) GR 活性介导大鼠中与 HIV gp120 和酒精依赖相关的痛觉过敏 (2) 循环皮质醇水平与 PLWH 的疼痛症状和 AUD 风险测量相关。 这项研究的结果将增进我们对应激激素信号在相互作用中的作用的理解 在强大的指导团队和 NIH P60 的支持下，研究了与 HIV 和酒精相关的疼痛之间的关系。 综合酒精-艾滋病毒/艾滋病研究中心（CARC），完成拟议的研究和培训 该计划将确保申请人为学术医学领域有影响力的职业做好准备。