SMART HAND

描述(申请人提供)：本共享调查员R01是5 P01 NS043985-09的扩展。目前的工作建立在开发长效纳米配方抗逆转录病毒疗法(NanoArt)的先前成功的基础上，以改善老年病毒感染者的药物输送和治疗结果。阐明衰老、艾滋病毒疾病和抗逆转录病毒治疗之间的相互作用是该项目的首要目标。可以使用工具来解决这种相互作用，这可以简化药物方案并改善疾病结果。首先，NanoArt可用于抗逆转录病毒反应以及中枢神经系统(CNS)和广泛代谢功能的长期测试。其次，跨学科的生物成像、行为和纳米药剂学可以评估病毒、药物、免疫和年龄相关的毒性。第三，可以通过PXR人源化(用人的细胞色素PYP3A4取代小鼠的CYP3A的雄甾烷受体)来测量药物在啮齿动物体内的药代动力学、药效学和药物相互作用。这可以用来评估长期免疫和抗病毒反应。第四，发现了一种新的工具，旨在改善对病毒库的ART传递，用于治疗(同时诊断和治疗)。这个系统被称为小磁铁ART(或SMART)，可以通过成像测试来分析药物的生物分布。这种成果措施将改善抗逆转录病毒治疗、中枢神经系统和淋巴系统的交付，从而与持续的艾滋病毒-1感染作斗争。聚集了一群有合作经验的调查人员。他们包括神经科学家(H.Gendelman，Co-Pi)、免疫病理学家(L.Pluektova，Co-Pi)、衰老和认知行为研究人员(S.Bonasera)、生物成像专家(M.Boska)、神经退行性疾病专家(R.L.Mosley)以及纳米医学和药物输送专家(X.Liu)。这项工作是及时和相关的。虽然抗逆转录病毒疗法大大降低了HIV感染的发病率和死亡率，同时也减少了病毒和免疫保护，但神经认知障碍和药物毒性的流行仍然很常见。事实上，50岁的病毒感染者数量翻了一番就在我们头上。新的并存疾病现在包括脑血管疾病、非艾滋病恶性肿瘤、胰岛素抵抗、高脂血症、痴呆症以及肝、肾和骨骼疾病。这就要求建立与当前艾滋病毒/艾滋病趋势相关的疾病研究的新模式系统。事实上，这项工作反映了人类疾病不断变化的流行病学模式。[我们承认，先前提交的材料缺乏关于我们的人性化大脑模型和纳米配方以及动物对治疗的反应的初步数据和细节。现在收录了一些最近的出版物和重要的新的初步数据，以透彻和合理的方式处理这些关切。]解决艾滋病毒和老龄化相关问题所需的工具也可供研究。

DESCRIPTION (provided by applicant): This shared investigator R01 is an extension of 5 P01 NS043985-09. The current work builds on prior successes in developing long-acting nanoformulated antiretroviral therapies (nanoART) to improve drug delivery and therapeutic outcomes for aged virus-infected people. Elucidating the interplay between aging, HIV disease and ART is the overarching project goal. The tools are available to address this interplay which can simplify drug regimens and improve disease outcomes. First, nanoART is available for long- term testing of antiretroviral responses together with central nervous system (CNS) and broad metabolic functions. Second, interdisciplinary bioimaging, behavior, and nanopharmaceutics can evaluate virus, drug, immune, and age-related toxicities. Third, drug pharmacokinetic, pharmacodynamics, drug-drug interactions can be measured by employing PXR humanization (the androstane receptor with replacement of the mouse Cyp3a with human CYP3A4) in rodents. This can be used to evaluate long-term immune and antiviral responses. Fourth, a novel tool designed to improve ART delivery to viral reservoirs was discovered for theranostics (simultaneous diagnostics and therapeutics). This system is called small magnetite ART (or SMART) and permits assay of drug biodistribution by imaging tests. Such outcome measures would improve ART CNS and lymphoid delivery and thus combat persistent HIV-1 infection. A group of investigators with productive histories of working together was assembled. They include neuroscientists (H. Gendelman, Co- PI), immunopathologists (L. Poluektova, Co-PI), aging and cognitive behavior researchers (S. Bonasera), bioimaging experts (M. Boska) those with expertise in neurodegenerative diseases (R. L. Mosley), and experts in nanomedicine and drug delivery (X. Liu). The work is timely and relevant. Although ART has profoundly reduced morbidities and mortality for HIV infection coincident with virus reductions and immune preservation, the prevalence of neurocognitive impairments and drug toxicities remain common. Indeed, the doubling of virus-infected patients > 50 years of age is upon us. New co-morbid conditions now include cerebrovascular disease, non-AIDS malignancies, insulin resistance, hyperlipidemia, dementia, and liver, renal and bone disorders. This demands new model systems for disease studies relevant to current HIV/AIDS trends. Indeed, the work reflects the changing epidemiologic patterns of human disease. [We acknowledge that the prior submission lacked preliminary data and details about our humanized brain model and nanoformulations and response of the animals to treatments. A number of recent publications and significant new preliminary data are now included that addresses each of these concerns in a thorough and reasoned manner.] The tools that are needed to tackle relevant questions in HIV and aging are also available for study.