SMART HAND

智能手

基本信息

批准号：
8738559
负责人：
Howard E Gendelman
金额：
$ 62.58万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8738559
关键词：
AIDS neuropathy AIDS/HIV problem Address Affect Age Age-Years Aging Aging-Related Process Androstanes Animal Model Animals Anti-Retroviral Agents Antiviral Response Architecture Behavior Behavioral Biodistribution Biological Assay Biological Models Biological Preservation Bone Density Bone Diseases Brain CYP3A4 gene Cardiac Cardiovascular system Cells Cerebrovascular Disorders Cognitive aging Contrast Media Data Dementia Development Diagnostic Disease Disease Outcome Disease model Drug Delivery Systems Drug Evaluation Drug Formulations Drug Interactions Drug Kinetics Drug Targeting Drug toxicity Elements Epidemiology Evaluation Event Excision Functional disorder Funding Genomics Goals Grant HIV HIV Infections HIV-1 Hematopoietic stem cells Human Hyperlipidemia ITGAM gene Image Immune Immune response Immunity Impaired cognition Impairment Improve Access Infection Insulin Resistance Interdisciplinary Study Investigation Kidney Kidney Diseases Lead Life Ligands Link Liver diseases Lymphoid Lymphoid Tissue Magnetic Resonance Imaging Malignant Neoplasms Measures Medicine Metabolic Metals Modeling Monitor Morbidity - disease rate Mus Neoplastic liver Nervous System Physiology Neuraxis Neurocognitive Neurodegenerative Disorders Neurons Outcome Outcome Measure Patients Pattern Peripheral Pharmaceutical Preparations Pharmacodynamics Predisposition Prevalence Protease Inhibitor Publications Quality of life Recording of previous events Regimen Renal function Research Research Personnel Rodent Scheme Staging System Testing Therapeutic Tissues Toxic effect Toxicology Transgenic Mice Transgenic Organisms Transplantation Treatment Efficacy Validation Viral Virus Virus Diseases Weight Work age related aged antiretroviral therapy base bioimaging bone cell behavior central nervous system injury combat demographics design diphtheria toxin receptor drug development drug distribution expectation fetal gray matter human disease immune function improved liver function macrophage magnetite ferrosoferric oxide middle age mortality mouse model nanoformulation nanomedicine nanoparticle novel novel therapeutics particle promoter public health relevance receptor relating to nervous system response self-renewal senescence success sugar theranostics therapy development tool trend white matter

项目摘要

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.

描述（由申请人提供）：该共享研究者 R01 是 5 P01 NS043985-09 的扩展。目前的工作建立在先前开发长效纳米制剂抗逆转录病毒疗法（nanoART）的成功基础上，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疗法之间的相互作用是该项目的首要目标。这些工具可用于解决这种相互作用，从而简化药物治疗方案并改善疾病结果。首先，nanoART 可用于长期测试抗逆转录病毒反应以及中枢神经系统 (CNS) 和广泛的代谢功能。其次，跨学科的生物成像、行为和纳米药物可以评估病毒、药物、免疫和年龄相关的毒性。第三，药物药代动力学、药效学、药物相互作用可以通过在啮齿类动物中采用PXR人源化（用人CYP3A4取代小鼠Cyp3a的雄甾烷受体）来测量。这可用于评估长期免疫和抗病毒反应。第四，发现了一种旨在改善 ART 向病毒库的传递的新工具，用于治疗诊断（同时诊断和治疗）。该系统称为小磁铁矿 ART（或 SMART），允许通过成像测试来测定药物的生物分布。此类结果措施将改善 ART 中枢神经系统和淋巴输送，从而对抗持续的 HIV-1 感染。一群具有丰富合作经验的调查人员聚集在一起。他们包括神经科学家（H. Gendelman，Co-PI）、免疫病理学家（L. Poluektova，Co-PI）、衰老和认知行为研究人员（S. Bonasera）、生物成像专家（M. Boska）以及神经退行性疾病方面的专业知识（R. L. Mosley）和纳米医学和药物输送专家（X. Liu）。这项工作是及时且相关的。尽管抗逆转录病毒治疗大大降低了艾滋病毒感染的发病率和死亡率，同时减少了病毒数量并保留了免疫功能，但神经认知障碍和药物毒性的普遍存在。事实上，50 岁以上的病毒感染患者人数将增加一倍。新的共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、痴呆以及肝脏、肾脏和骨骼疾病。这需要与当前艾滋病毒/艾滋病趋势相关的疾病研究新模型系统。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。 [我们承认之前提交的材料缺乏有关我们的人性化大脑模型和纳米制剂以及动物对治疗的反应的初步数据和细节。现在包括了一些最近的出版物和重要的新初步数据，以彻底和合理的方式解决了这些问题。]解决艾滋病毒和老龄化相关问题所需的工具也可供研究。