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; 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奖学金将使申请人为成功的职业做好准备，作为翻译的身体 - 科学家。职业发展培训将集中于高优先级艾滋病毒/艾滋病合并症相关的研究， 使用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（PLWH）的人群。酒精使用障碍（AUD）是一种慢性疾病 饮酒过多，经常在患有艾滋病毒（PLWH）的患者中合并。 AUD经常导致 影响消耗酒精欲望的负面情绪状态的出现，一种可能 PLWH中这些负面情感状态的重要因素是与HIV相关的疼痛神经病（HIV- n）。那，在PLWH中喝酒的基本原理可能源于对由于 酒精的镇痛特性。重要的是，多余的饮酒也会导致痛觉过敏 HIV-N可能会忘记这。先前的工作描述了动物中的痛觉过敏的出现 取决于酒精。 PLWH队列中的初步研究也揭示了正相关 在审计（酒精使用障碍识别测试）之间的分数和应力的循环水平之间 皮质醇。在分子水平上，糖皮质激素受体（GRS）的转录活性直接控制 通过磷酸化状态。 GR信号传导的失调可能有助于促进AUD的过渡并有助于 听到相关的痛觉过敏，可能在HIV-N的发展中发挥作用。此外，慢性疼痛 可以在大脑区域中导致脊柱上的可塑性，与伤害感受和负面情绪联系在一起，例如 扣带皮层，这也可能有助于AUD的建立或发展。为此， 初步数据发现酒精依赖性大鼠的扣带中GR磷酸化的增加。 为了研究酒精和艾滋病毒对HIV-N的贡献，我们利用了已建立的临床前啮齿动物模型 采用周围神经性暴露于HIV包膜蛋白，糖蛋白120（GP120），这密切涉及 在HIV-N的发病机理中。综上所述，我们的初步数据和现有文献支持 假设与艾滋病毒和高危饮酒有关的疼痛增加是由增强的驱动的 糖皮质激素受体（GR）活性。拟议的研究将采用多种技术来测试两个 假设：（1）GR活性介导了与HIV GP120相关的痛觉过敏和大鼠酒精依赖性 （2）循环皮质醇水平与PLWH中的疼痛症状和AUD风险度量有关。 这项研究的结果将提高我们对应力同源信号在相互作用中的作用的理解 在HIV和酒精相关的疼痛之间。在强大的心理团队和NIH P60的支持下 全面的酒精-HIV/AIDS研究中心（CARC），拟议的研究和培训的完成 计划将确保申请人为学术医学领域的有影响力的职业做好准备。