Pilot Proteomics Center for HIV-Related Dementia and Drug Abuse

描述(申请人提供)：在抗逆转录病毒(ARV)治疗的时代，艾滋病毒相关性痴呆症的临床症状已经演变为较慢的进展，临床和放射学参数缺乏监测疾病进展的敏感性。这对使用神经保护剂进行临床试验和管理这一患者群体提出了独特的挑战。基于蛋白质组学的生物标记物和替代标记物的发展至关重要，因为它们有望在细胞水平上对大脑功能的微小变化敏感。我们小组的初步数据表明，氧化应激导致的蛋白质翻译后修饰与认知功能障碍有关。质谱学的最新进展使得同时研究生物体液中的大量蛋白质并相对容易地鉴定蛋白质成为可能。利用这些独特的机会，拟议的艾滋病毒相关痴呆症和药物滥用试点蛋白质组学中心的首要主题是发现、确定和开发药物滥用患者艾滋病毒相关认知障碍和痴呆症的新生物标记物。基于我们的制度优势和在临床护理方面的持续重要性，我们已将这项工作确定为高度优先事项。约翰霍普金斯大学(JHU)已经有大量由研究人员发起的艾滋病毒神经科学研究，特别是专注于蛋白质组学、发病机制以及临床试验设计方面的重要专业知识。尽管有这种丰富的环境，但目前还没有普遍接受的、临床接受的可用于艾滋病毒相关认知障碍的生物标志物。在JHU蛋白质组学和艾滋病毒神经科学界内，生物标记物开发的潜在合作目前受到缺乏强有力的中央组织结构的限制，特别是缺乏将不同类型的研究联系起来并促进跨学科研究的设施。该中心将解决这些不足之处。我们提出了三个互动项目：1)将对一组明确的HIV感染吸毒者进行脑脊液蛋白质组分析。还将对有助于氧化应激途径的遗传标记进行初步研究。2)SIV脑炎模型的脑脊液蛋白质组学分析；3)HIV感染和药物滥用的体外人脑模型。 公共卫生相关性：该项目的目标是开发艾滋病毒感染药物滥用人群中认知功能障碍的高度敏感的生物标记物。我们将把我们的努力集中在鉴定在这些疾病状态下被独特修饰的蛋白质上。我们希望监测这些生物标志物将有助于我们在较短持续时间和较少患者数量的患者中进行临床试验。这将转化为更好的患者护理和预防这些患者的认知功能障碍。

DESCRIPTION (provided by applicant): During the era of antiretroviral (ARV) therapy, the clinical syndrome of HIV associated dementia has evolved to a slower progression whereby clinical and radiological parameters lack the sensitivity for monitoring disease progression. This has posed unique challenges for conducing clinical trials with neuroprotective agents and for managing this patient population. The development of proteomics based biomarkers and surrogate markers are critical since they hold the promise of being sensitive to minor changes in brain function at a cellular level. Preliminary data from our group suggest that post translational modifications in proteins as a result of oxidative stress correlate with cognitive dysfunction. Recent advances in mass spectrometry (MS) have made it feasible to study large numbers of proteins simultaneously in biological fluids and to identify the proteins with relative ease. Taking advantage of these unique opportunities, the overarching theme of the proposed Pilot Proteomics Center for HIV-related Dementia and Drug Abuse is the discovery, identification and development of novel biomarkers for HIV-associated cognitive disorders and dementia in drug abusing patients. We have identified this as a high priority on the basis of our institutional strengths and continuing importance in clinical care. There is already a wealth of investigator-initiated HIV neuroscience research at Johns Hopkins University (JHU), especially focused on proteomics, pathogenesis, as well as significant expertise in clinical trial design. Despite this rich environment, currently there are no universally accepted, clinically accepted biomarkers available for HIV-associated cognitive disorders. Within the JHU Proteomics and HIV Neuroscience community, potential collaborations for biomarker development are currently limited by the lack of a strong central organizing structure, and specifically a facility to link different types of research, and to facilitate cross-disciplinary research. This Center will address these deficiencies. We propose three interactive projects, 1) Cerebrospinal Fluid (CSF) proteomic analysis will be performed on a well defined cohort of HIV infected drug abusers. A pilot study on the genetic markers that contribute to oxidative stress pathways will also be examined. 2) Similar proteomics analysis in CSF from SIV encephalitis model and 3) An in vitro human brain model of HIV infection and drug abuse. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop highly sensitive biomarkers of cognitive dysfunction in HIV infected drug abusing populations. We will focus our efforts on the identification of proteins that are uniquely modified during these disease states. We hope that monitoring these biomarkers will help us conduct clinical trials in patients over shorter durations and with smaller numbers of patients. This will translate to better patient care and prevention of cognitive dysfunction in these patients.