Mechanisms of Interactions of Alcohol Abuse HIV Neuropathogenesis

酒精滥用与 HIV 神经发病机制的相互作用

• 批准号: 7687568
• 负责人: JON DAVID LEVINE
• 金额: $ 34.76万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687568
• 关键词: AIDS therapy; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Adverse effects; Affect; Afferent Neurons; Alcohol abuse; Alcohol consumption; Alcohols; Anti-Retroviral Agents; Applications Grants; Chronic Disease; Development; Diet; Dose; Effectiveness; Elements; Exposure to; Foundations; Functional disorder; Goals; HIV; Highly Active Antiretroviral Therapy; Hyperalgesia; Individual; Integration Host Factors; Investigation; Medical; Nerve Fibers; Nervous system structure; Neurologic; Neuronal Dysfunction; Neuropathogenesis; Neuropathy; Neurosecretory Systems; Nociceptors; Nucleosides; Pain; Pathway interactions; Patients; Peripheral Nervous System; Peripheral Nervous System Diseases; Physiological; Play; Prevalence; Prevention; Proteins; Quality of life; Research; Research Proposals; Risk Factors; Rodent Model; Role; Second Messenger Systems; Severities; Stress; Testing; Toxic effect; Viral; Withdrawal; Writing; alcohol effect; alcohol exposure; alcohol measurement; antiretroviral therapy; clinically relevant; design; effective therapy; improved; mitochondrial dysfunction; nerve injury; neurotoxicity; novel therapeutics; painful neuropathy; public health relevance; response; second messenger; treatment strategy

DESCRIPTION (provided by applicant): This grant application is written in response to RFA-AA-07-015 "Mechanisms of Nervous System Dysfunction: Impact of Alcohol Abuse on HIV-Neuropathogenesis (R01)," the stated intent of which is "to encourage applications that will determine the effects of abusive alcohol consumption on the abilities of viral encoded proteins and/or host factors to cause the neuronal dysfunction and damage that produces HIV-associated neurological complications" including painful "antiretroviral toxic neuropathy (ATN) that results from neurotoxicity caused by antiretroviral therapy." Alcohol abuse is one of the most important comorbid risk factors for peripheral neuropathy in patients receiving therapy for HIV/AIDS. Despite the prevalence of this problem and its serious impact on the quality of life and therapy in HIV patients, the mechanisms by which alcohol abuse exacerbates HAART-induced neuropathic pain has not been investigated. To create a foundation for the rational design of new therapeutic strategies to treat alcohol-exacerbated neuropathic pain in HIV/AIDS patients, we propose to investigate the cellular mechanisms by which consumed alcohol aggravates antiretroviral-induced neuropathic pain. These studies will employ our well-established clinically relevant rodent models of HIV/AIDS therapy induced painful peripheral neuropathy, and neuropathic effects of alcohol abuse and withdrawal to create a foundation for the rational design of new mechanism-targeted strategies for the treatment and prevention of HAART induced neuropathic pain in patients who abuse alcohol. Our preliminary investigations clearly demonstrate that exposure to even moderate levels of alcohol in the diet dramatically increases the severity of antiretroviral-induced neuropathic pain. We propose to focus our investigation on the detailed analysis of the second messenger mechanisms and mitochondrial dysfunction in sensory neurons that underlie the effect of alcohol on antiretroviral-induced painful hyper-excitability of nerve fibers. In addition, because our preliminary investigations suggest that physiological stress pathways play a crucial role in the neurological effect of alcohol, we will also analyze the contributions of elements of these pathways. Our ultimate goal is that by improving the medical management of painful peripheral neuropathy in HIV/AIDS patients, this research will contribute to improving the quality of life, and the effectiveness of HAART therapy in HIV/AIDS patients. Public Health Relevance: The research that we propose to perform is designed to determine whether alcohol consumption affects the ability to treat patients with the most effective therapy available for AIDS, highly active antiretroviral therapy (HAART). With the development of HAART, AIDS has been converted from an often-fatal acute illness to a chronic disease. Unfortunately, HAART can cause nerve injury, producing severe pain as a side effect, which may require decreasing doses or even stopping this highly effective therapy. Since patients with AIDS are much more likely to use and abuse alcohol than individuals who do not have AIDS, and alcohol also has toxic effects on the peripheral nervous system, including painful peripheral neuropathy, the goal of this research proposal is to investigate how alcohol use exacerbates HAART-induced neuropathic pain in patients with AIDS. These studies will provide detailed information on how alcohol consumption can produce neuropathic pain in AIDS patients receiving HAART therapy. Our ultimate goal is to provide a foundation for the design of approaches to treat this threat to the quality of life of AIDS patients.

描述（由申请人提供）：该赠款的申请是根据RFA-AA-07-015编写的，“神经系统功能障碍的机制：酗酒对HIV - 神经病生成的影响（R01）”，其陈述的意图是“鼓励确定滥用酒精对病毒蛋白和/或宿主的能力的影响的应用，以确定滥用型和/或施用病毒蛋白的影响。产生与艾滋病毒相关的神经系统并发症的损害“包括疼痛的”抗逆转录病毒毒性神经病（ATN），这是由抗逆转录病毒疗法引起的神经毒性导致的。酒精滥用是接受HIV/AIDS治疗的患者周围神经病的最重要的合并风险因素之一。尽管这个问题的普遍性及其对艾滋病毒患者生活质量和治疗的严重影响，但尚未研究酗酒加剧HAART引起的神经性疼痛的机制。为了为艾滋病毒/艾滋病患者治疗饮酒的神经性疼痛的新治疗策略的合理设计创造基础，我们建议研究细胞机制，通过这种机制，消耗的酒精会加剧抗逆转录病毒诱导的神经性疼痛。这些研究将采用我们建立的临床相关的艾滋病毒/艾滋病治疗诱导的疼痛神经性神经病，以及酗酒和戒断的神经病作用，为HAART诱导滥用酒精的患者的神经病治疗的新机制治疗和预防的新机制策略的合理设计创造了基础。我们的初步研究清楚地表明，饮食中甚至中等水平的酒精暴露会大大增加抗逆转录病毒引起的神经性疼痛的严重程度。我们建议将调查重点放在对第二个信使机制和线粒体功能障碍的详细分析上，这是酒精对抗逆转录病毒诱导的神经纤维疼痛疼痛的高效果的影响的基础。此外，由于我们的初步研究表明生理压力途径在酒精的神经系统作用中起着至关重要的作用，因此我们还将分析这些途径元素的贡献。我们的最终目标是，通过改善艾滋病毒/艾滋病患者的疼痛周围神经病的医疗管理，这项研究将有助于改善生活质量，以及HAART治疗在HIV/AIDS患者中的有效性。 公共卫生相关性：我们建议进行的研究旨在确定饮酒是否影响治疗可用于艾滋病最有效疗法的患者，高度活跃的抗逆转录病毒疗法（HAART）。随着HAART的发展，AIDS已从经常致命的急性疾病转化为慢性疾病。不幸的是，HAART会引起神经损伤，从而导致严重的疼痛作为副作用，这可能需要减少剂量，甚至停止这种高效的治疗。由于与没有艾滋病的人相比，患有艾滋病的患者使用和滥用酒精的可能性更大，而且酒精对周围神经系统（包括疼痛的周围神经病）也具有毒性作用，因此该研究建议的目的是调查酒精使用如何加剧HAART诱导HAART诱导的艾滋病患者的神经性疼痛。这些研究将提供有关饮酒如何在接受HAART治疗的艾滋病患者中产生神经性疼痛的详细信息。我们的最终目标是为设计艾滋病患者生活质量的这种威胁的方法设计基础。