Manganese Enhanced Multi-MRI for Murine HIV-1 Associated Neurocognitive Disorders

锰增强多重 MRI 治疗小鼠 HIV-1 相关神经认知障碍

• 批准号: 8204975
• 负责人: Yutong Liu
• 金额: $ 13.96万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204975
• 关键词: AIDS Dementia Complex; AIDS neuropathy; Address; Affect; Algorithms; Anatomy; Animals; Astrocytosis; Atrophic; Attenuated; Award; Axon; Behavioral; Biochemical; Biological Markers; Biomedical Research; Brain; Brain imaging; Cells; Characteristics; Chronic; Clinical; Cognitive; Cognitive deficits; Data Analyses; Dementia; Detection; Development; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Disease model; Doctor of Philosophy; Dose; Drops; Edema; Encephalitis; Engineering; Engraftment; Event; Faculty; Fiber; Focal Infection; Foundations; Functional disorder; Generations; Giant Cells; Goals; HIV-1; Highly Active Antiretroviral Therapy; Histology; Histopathology; Human; Image; Imagery; Imaging technology; Impairment; Incidence; Infection; International; Laboratories; Macrophage Activation; Magnetic Resonance; Magnetic Resonance Imaging; Manganese; Maps; Mathematics; Measures; Medical Imaging; Medical center; Mentors; Methods; Metric; Microglia; Microscopic; Microscopy; Modeling; Monitor; Morphology; Motor; Mus; Myelin; Nebraska; Nervous system structure; Neuroanatomy; Neurocognitive; Neurodegenerative Disorders; Neurologic; Neurologic Dysfunctions; Neurons; Neurosciences; Noise; Operative Surgical Procedures; Pallor; Pathology; Pathway interactions; Patients; Physiological; Physiology; Prevalence; Procedures; Process; Radiology Specialty; Relaxation; Research; Research Personnel; Research Project Grants; Resolution; Scanning; Severe Combined Immunodeficiency; Signal Transduction; Signs and Symptoms; Slice; Solid; Staging; Staining method; Stains; Stem cells; Structure; Synapses; Techniques; Testing; Therapeutic; Time; Training; Training and Education; United States National Institutes of Health; Universities; Viral; Viral Encephalitis; Virus; Virus Diseases; Weight; Western World; Xenograft procedure; antiretroviral therapy; astrogliosis; authority; brain volume; career; density; environmental change; experience; gray matter; image processing; in vivo; irradiation; macrophage; manganese chloride; member; nervous system disorder; neuroinflammation; neuron loss; neuropsychological; neurotoxicity; novel; post-doctoral training; public health relevance; theories; ultra high resolution; uptake; water diffusion; white matter

DESCRIPTION (provided by applicant): The candidate, Yutong Liu PhD, is a junior faculty member in the Radiology Department with a strong background in engineering and mathematics, MRI theory, and medical image processing. Dr Liu has had extensive experience in the application of MRI and development of novel image processing methods both during his post-doctoral training and his first years as a junior faculty member. This provides him a solid foundation for biomedical research, but to develop as an independent investigator in neuroscience he requires training in basic neuroscience and practical aspects of performing animal studies. Dr. Liu has assembled a strong mentor and collaborator team with an excellent track record in MRI, neuroscience and image processing research. His primary mentor, Dr. Michael Boska is a leading expert in MRI and MRS. His co-mentor, Dr. Howard Gendelman is an international authority in neurodegenerative diseases. In addition, Dr. Liu will take graduate level courses in neuroscience provided in UNMC. The research project addresses an imperative need in NeuroAIDS research as detailed below. This project will provide training for Dr. Liu in 1) murine brain anatomy and physiology, 2) generation of disease models in mice including irradiation, human cell engraftment, cell acquisition, cultivation, infection and animal surgery, 3) immunohistochemical processing and analysis including, but not limited to slicing, staining and quantification of histopathological staining used for interpretation of results. Dr. Liu will submit a R01 to the NIH by the end of Year 3 of the award focused on the study of neurodegenerative diseases using advanced imaging technologies. His long term career goal is to become an independent investigator in neuroscience. HIV-1 associated neurocognitive disorders (HAND) occurs in the late stage HIV-1 infection and manifests with varying degrees of clinical cognitive, behavioral and motor abnormalities. These range from mild motor/cognitive deficits to overt dementia (HIV-1 associated dementia, HAD). With antiretroviral therapy the cumulative incidence is 25-38% and the prevalence is around 37%. Milder forms affect an additional 30-40% of patients. The chronic and fluctuating forms of HIV dementia are more common. The pathological correlate of HAD is HIV-1 encephalitis (HIVE). The presence of activated microglia and brain macrophages with lower levels of virus is a central pathological feature of disease. Tests that can clearly distinguish HAND from other diseases of the nervous system that occur during progressive HIV-1 infection are needed for definitive diagnosis, disease progression tracking and therapeutic monitoring. Murine models of HIVE and HAND have been developed at the University of Nebraska Medical Center. The objective of this proposal is to develop in-vivo manganese enhanced 3D multispectral magnetic resonance microscopy (MRM) that will serve as a biomarker for HAND. In vivo manganese enhanced multispectral MRM (MEmMRM) and MRM data analysis techniques will be developed to determine the time course of neuronal loss, macrophage/microglial activation and astrocytosis in the murine HIVE and HAND models. MEmMRM results in diseased mice will be confirmed with controls and histopathological analysis. PUBLIC HEALTH RELEVANCE: The cumulative incidence of HIV-1 associated dementia in the Western world is 25-38% with highly active antiretroviral therapy (HAART) and the prevalence is around 37%. Milder forms affect an additional 30-40% of patients. Although a number of clinical, laboratory and radiological tests are available to aid in diagnosis, none are conclusive. This project will provide a biomarker of HIV-1 associated neurocognitive disorders for definitive diagnosis, disease progression tracking and therapeutic monitoring using MRI on murine models.

描述（由申请人提供）： 候选人刘雨桐博士是放射科的一名初级教员，具有深厚的工程和数学、MRI 理论和医学图像处理背景。刘博士在博士后培训期间和初级教员的最初几年在 MRI 应用和新型图像处理方法的开发方面拥有丰富的经验。这为他的生物医学研究奠定了坚实的基础，但要发展成为神经科学的独立研究者，他需要接受基础神经科学和进行动物研究的实践方面的培训。刘博士组建了一支强大的导师和合作团队，在 MRI、神经科学和图像处理研究方面拥有出色的业绩记录。他的主要导师 Michael Boska 博士是 MRI 和 MRS 领域的领先专家。他的合作导师 Howard Gendelman 博士是神经退行性疾病领域的国际权威。此外，刘博士还将学习 UNMC 提供的神经科学研究生课程。该研究项目满足了 NeuroAIDS 研究的迫切需求，详情如下。该项目将为刘博士提供以下方面的培训：1) 小鼠脑解剖和生理学，2) 小鼠疾病模型的生成，包括辐射、人类细胞植入、细胞采集、培养、感染和动物手术，3) 免疫组织化学处理和分析，包括，但不限于用于解释结果的切片、染色和组织病理学染色的定量。刘博士将在该奖项的第三年年底之前向 NIH 提交 R01，重点是使用先进成像技术研究神经退行性疾病。他的长期职业目标是成为神经科学领域的独立研究者。 HIV-1相关神经认知障碍（HAND）发生在HIV-1感染晚期，表现为不同程度的临床认知、行为和运动异常。这些范围从轻度运动/认知缺陷到明显的痴呆（HIV-1 相关痴呆，HAD）。通过抗逆转录病毒治疗，累积发病率为 25-38%，患病率为 37% 左右。较温和的形式影响另外 30-40% 的患者。慢性和波动性的艾滋病毒痴呆更为常见。 HAD 的病理相关性是 HIV-1 脑炎 (HIVE)。病毒水平较低的激活的小胶质细胞和脑巨噬细胞的存在是疾病的核心病理特征。为了明确诊断、疾病进展跟踪和治疗监测，需要进行能够清楚地区分 HAND 与进行性 HIV-1 感染期间发生的其他神经系统疾病的测试。内布拉斯加大学医学中心开发了 HIVE 和 HAND 小鼠模型。该提案的目标是开发体内锰增强 3D 多光谱磁共振显微镜 (MRM)，作为 HAND 的生物标志物。将开发体内锰增强多光谱 MRM (MEmMRM) 和 MRM 数据分析技术，以确定小鼠 HIVE 和 HAND 模型中神经元损失、巨噬细胞/小胶质细胞激活和星形细胞增多的时间过程。患病小鼠的 MEmMRM 结果将通过对照和组织病理学分析得到证实。 公共卫生相关性：在西方世界，采用高效抗逆转录病毒疗法 (HAART) 后，HIV-1 相关痴呆的累积发病率为 25-38%，患病率约为 37%。较温和的形式影响另外 30-40% 的患者。尽管许多临床、实验室和放射学测试可帮助诊断，但没有一个是结论性的。该项目将提供 HIV-1 相关神经认知障碍的生物标志物，用于在小鼠模型上使用 MRI 进行明确诊断、疾病进展跟踪和治疗监测。