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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

基本信息

批准号：
8593313
负责人：
Yutong Liu
金额：
$ 14.84万
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：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8593313
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

项目摘要

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.

简介（申请人提供）：候选人刘宇桐博士，放射科初级教员，具有工程、数学、核磁共振理论、医学图像处理等方面的深厚背景。刘博士在博士后培训期间和作为初级教员的第一年，在MRI应用和新型图像处理方法的开发方面都有丰富的经验。这为他的生物医学研究奠定了坚实的基础，但要成为一名独立的神经科学研究者，他需要接受基础神经科学和动物研究实践方面的培训。刘博士组建了一个强大的导师和合作者团队，在MRI，神经科学和图像处理研究方面有着出色的记录。他的主要导师Michael Boska博士是MRI和mrs领域的权威专家，他的共同导师Howard Gendelman博士是神经退行性疾病领域的国际权威。此外，刘博士将参加UNMC提供的神经科学研究生课程。该研究项目解决了神经艾滋病研究的迫切需要，详情如下。该项目将为刘博士提供以下方面的培训：1)小鼠脑解剖学和生理学；2)小鼠疾病模型的生成，包括辐照、人细胞植入、细胞获取、培养、感染和动物手术；3)免疫组织化学处理和分析，包括但不限于切片、染色和用于解释结果的组织病理学染色的定量。Liu博士将在该奖项的第三年年底向NIH提交R01，专注于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一名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感染的晚期，表现为不同程度的临床认知、行为和运动异常。这些范围从轻微的运动/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，累计发病率为25-38%，患病率约为37%。较轻的形式影响另外30-40%的患者。慢性和波动形式的艾滋病毒痴呆更为常见。HAD的病理相关是HIV-1脑炎（HIVE）。激活的小胶质细胞和具有较低水平病毒的脑巨噬细胞的存在是该疾病的主要病理特征。对于明确诊断、疾病进展跟踪和治疗监测，需要能够明确区分HAND与进展性HIV-1感染期间发生的其他神经系统疾病的检测。内布拉斯加州大学医学中心开发了HIVE和HAND的小鼠模型。该提案的目的是开发体内锰增强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模型中神经元丢失、巨噬细胞/小胶质细胞激活和星形细胞增殖的时间过程。患病小鼠的MEmMRM结果将通过对照和组织病理学分析来证实。