Pilot Proteomics Center for HIV-Related Dementia and Drug Abuse

描述（由申请人提供）：在抗逆转录病毒（ARV）治疗期间，HIV相关痴呆的临床综合征进展较慢，临床和放射学参数缺乏监测疾病进展的灵敏度。这对进行神经保护剂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志物和替代标志物的发展是至关重要的，因为它们有望在细胞水平上对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相关。质谱（MS）的最新进展使得同时研究生物液体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，鉴定和开发药物滥用患者中艾滋病毒相关认知障碍和痴呆症的新型生物标志物。我们已经确定这是一个高度优先的基础上，我们的机构优势和临床护理的持续重要性。在约翰霍普金斯大学（JHU）已经有大量的艾滋病毒神经科学研究，特别是集中在蛋白质组学，发病机制，以及临床试验设计的重要专业知识。尽管有这种丰富的环境，目前还没有普遍接受的，临床上接受的生物标志物可用于艾滋病毒相关的认知障碍。在JHU蛋白质组学和HIV神经科学社区内，生物标志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，特别是缺乏连接不同类型研究的设施，并促进跨学科研究。该中心将解决这些缺陷。我们提出了三个互动的项目，1）脑脊液（CSF）蛋白质组学分析将进行一个明确的队列艾滋病毒感染的药物滥用者。还将研究有助于氧化应激途径的遗传标记的试点研究。2)来自SIV脑炎模型的CSF中的相似蛋白质组学分析和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HIV感染的药物滥用人群中认知功能障碍的高度敏感的生物标志物。我们将集中精力鉴定在这些疾病状态下独特修饰的蛋白质。我们希望监测这些生物标志物将有助于我们在更短的时间内和更少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.