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）：该共享的研究者R01的扩展名为5 P01 NS043985-09。目前的工作是基于发展长效纳米成型抗逆转录病毒疗法（NANOART）的成功，以改善对年龄病毒感染者的药物递送和治疗结果。阐明衰老，艾滋病毒疾病和艺术之间的相互作用是总体项目目标。这些工具可用于解决此相互作用，该工具可以简化药物方案并改善疾病结果。首先，NanoART可用于与中枢神经系统（CNS）和广泛的代谢功能一起对抗逆转录病毒反应进行长期测试。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，免疫和与年龄有关的毒性。第三，可以通过在啮齿动物中使用PXR人性化（用小鼠CYP3A替换小鼠CYP3A）来测量药物药代动力学，药效学，药物 - 药物相互作用。这可用于评估长期免疫和抗病毒反应。第四，一种新型工具，旨在改善用于病毒储层的艺术品（同时诊断和治疗学）。该系统称为小磁铁矿艺术（或智能），并允许通过成像测试对药物生物分布进行测定。这种结果度量将改善ART中枢神经系统和淋巴输送，从而改善持续的HIV-1感染。组装了一组具有生产历史的研究人员。 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).这项工作是及时且相关的。尽管ART严重降低了与病毒降低和免疫保存相吻合的HIV感染的病态和死亡率，但神经认知障碍和药物毒性的流行仍然很普遍。实际上，感染了50岁的病毒感染患者的加倍正在我们身上。现在的新合并状况包括脑血管疾病，非AID恶性肿瘤，胰岛素抵抗，高脂血症，痴呆和肝脏，肾脏和骨骼疾病。这需要与当前的艾滋病毒/艾滋病趋势有关的疾病研究的新模型系统。实际上，这项工作反映了人类疾病的流行病学模式不断变化。 [我们承认，先前的提交缺乏有关我们人性化大脑模型以及动物对治疗的纳米化和反应的初步数据和详细信息。现在包括许多最近的出版物和重要的新初步数据，这些数据以彻底和合理的方式解决了这些问题的每一个。