Immune Activation, Cerebral Metabolic Activity and Depression in Treated HIV-Infection

HIV 感染治疗中的免疫激活、大脑代谢活动和抑郁

基本信息

批准号：
10339397
负责人：
Shibani Sharon Mukerji
金额：
$ 18.52万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10339397
关键词：
Acquired Immunodeficiency Syndrome Address Adult Advisory Committees Affect Americas Antidepressive Agents Award Bioinformatics Biological Biological Assay Biological Factors Biometry Blood Brain Brain imaging Brain region CD14 gene Cell Surface Receptors Cells Cerebrum Chronic Clinical Communicable Diseases Computational Biology Computer Analysis Computer Models Corpus striatum structure Coupled Cross-Sectional Studies Data Data Set Depressive disorder Disease Dopamine FCGR3B gene Functional disorder Funding Generations Glucose Goals HIV HIV Infections HIV-1 HIV-associated cognitive impairment Host Defense Human Human immunodeficiency virus test Immune Immune system Immunity Immunologic Markers Immunologics Immunology Impaired cognition In Vitro Individual Infiltration Inflammation Infrastructure Integration Host Factors K-Series Research Career Programs Learning Link Longitudinal cohort Lymphocyte Medical Mental Depression Mentored Patient-Oriented Research Career Development Award Mentors Mentorship Metabolic Metabolic Diseases Metabolic Pathway Molecular Biology Morbidity - disease rate National Institute of Mental Health National NeuroAids Tissue Consortium Nervous System Physiology Neuraxis Neuroimmune Neurologic Neurologic Symptoms Neurologist Neurons Neuropathogenesis Neurosciences Participant Pathogenesis Patients Persons Physicians Positioning Attribute Positron-Emission Tomography Prefrontal Cortex Preparation Process Prognostic Marker Randomized Research Research Personnel Research Proposals Risk Role Scientist Senior Scientist Societies Symptoms T-Lymphocyte Testing Thalamic structure Training United States National Institutes of Health Viral World Health Organization antiretroviral therapy career cingulate cortex clinical effect cohort depressive symptoms double-blind placebo controlled trial fluorodeoxyglucose fluorodeoxyglucose positron emission tomography image archival system imaging study immune activation innovative technologies insight interest large scale data metabolome metabolomics microbial monoamine monocyte multidisciplinary nervous system disorder neuroimaging neuropsychiatric symptom new therapeutic target novel novel diagnostics patient subsets predictive marker predictive signature prognostic signature programs relating to nervous system

项目摘要

Project Summary Depression is a critical medical challenge affecting the morbidity of millions of people living with HIV despite availability of effective antiretroviral therapy (ART). Subsets of patients with depressive disorders do not respond to traditional antidepressant treatments, potentially reflecting disease mechanisms not addressed with standard therapy. This multidisciplinary proposal seeks to understand the interactions between host factors and neurological function by identifying metabolic pathways altered in depression using novel high-throughput metabolite profiling coupled with neuroimaging and immunological studies. This K23 Mentored Clinical Scientist Research Career Development Award details a comprehensive five-year program for the candidate to acquire formal training and mentorship with specific expertise in advanced computational modeling, and immunity and host defense. In this K23 proposal, the candidate will carry out a neurological substudy within the framework of a randomized, double-blind, placebo controlled trial in participants with HIV infection. First, the candidate aims to study cerebral function by positron emission tomography (PET) imaging with 2- [18F]-fluorodeoxyglucose (FDG), a sensitive indicator of neural activity and will define relationships with immune cell markers and depression. Second, the candidate seeks to determine the influence of monocyte subsets and activated T-lymphocytes on depression in treated chronic HIV-infection. Third, by studying the blood metabolome from HIV-infected individuals with depression in cross-sectional analysis and validating findings in an independent longitudinal cohort, the candidate will learn how systemic byproducts of metabolic pathways may be used to identify people living with HIV who are “at risk” for persistent depressive symptoms. During the course of the award, the candidate will explore systemic metabolic pathways influencing depression in HIV-infected adults on ART with the goal of identifying potential novel diagnostic and therapeutic targets. The candidate is a board-certified neurologist with prior doctoral training in molecular biology and neuroscience. In preparation for an independent research career, the candidate will complete training in bioinformatics for analyzing large-scale datasets, and immunology through coursework and analysis of clinical, biological and metabolite data derived from the neurological substudy and multiple existing cohorts with chronic HIV infection. The candidate’s training will be guided by established mentors in the field of HIV infection and an advisory committee of senior scientists with collective expertise in HIV-associated neuropathogenesis and metabolic disease, metabolomics, computational modeling, bioinformatics, biostatistics, and neuroimaging.

项目概要抑郁症是一个严重的医学挑战，影响着数百万患有抑郁症的人的发病率尽管有有效的抗逆转录病毒治疗（ART），抑郁症患者仍感染艾滋病毒。疾病对传统的抗抑郁治疗没有反应，可能反映了疾病该多学科提案旨在了解标准疗法未解决的机制。通过识别代谢途径来研究宿主因素与神经功能之间的相互作用使用新型高通量代谢物分析结合神经影像学改变抑郁症免疫学研究。 K23 指导临床科学家研究职业发展奖详细介绍了全面的五年计划，让候选人获得正规培训和指导高级计算建模、免疫和宿主防御方面的具体专业知识在此 K23 中。提案中，候选人将在随机、对艾滋病毒感染者进行双盲、安慰剂对照试验首先，候选人的目的是研究。使用 2-[18F]-氟脱氧葡萄糖进行正电子发射断层扫描 (PET) 成像来评估脑功能（FDG），神经活动的敏感指标，将定义与免疫细胞标记物和其次，候选人试图确定单核细胞亚群和抑郁症的影响。第三，通过研究血液，激活 T 淋巴细胞对治疗慢性 HIV 感染的抑郁症的影响。 HIV感染者抑郁症代谢组的横断面分析和验证在独立纵向队列中的发现中，候选人将了解系统性副产品如何代谢途径可用于识别艾滋病毒感染者，他们是否“面临持续感染风险” 抑郁症状。在获奖过程中，候选人将探索全身代谢途径影响接受 ART 治疗的 HIV 感染者的抑郁症，目的是发现潜在的新奇候选人是具有博士学位的委员会认证的神经科医生。分子生物学和神经科学方面的培训为独立研究生涯做准备。候选人将完成用于分析大规模数据集的生物信息学和免疫学培训通过课程作业和对来自临床、生物和代谢数据的分析神经学亚组研究和多个现有的慢性 HIV 感染队列。将由艾滋病毒感染领域的知名导师和高级顾问委员会指导在艾滋病毒相关神经发病机制和代谢疾病方面拥有集体专业知识的科学家，代谢组学、计算模型、生物信息学、生物统计学和神经影像学。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Gastrointestinal Dysfunction and HIV Comorbidities.

DOI：
10.1007/s11904-020-00537-8
发表时间：
2021-03
期刊：
Current HIV/AIDS reports
影响因子：
4.6
作者：
Sim JH;Mukerji SS;Russo SC;Lo J
通讯作者：
Lo J

Mechanisms of Entry Into the Central Nervous System by Neuroinvasive Pathogens.

DOI：
10.1097/wno.0000000000001455
发表时间：
2022-06-01
期刊：
Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society
影响因子：
0
作者：
通讯作者：

What can we learn from brain autopsies in COVID-19?

DOI：
10.1016/j.neulet.2020.135528
发表时间：
2021-01-18
期刊：
Neuroscience letters
影响因子：
2.5
作者：
Mukerji SS;Solomon IH
通讯作者：
Solomon IH

Steroid-sparing agents for the treatment of inflammation in complicated neurocysticercosis.

用于治疗复杂性神经囊尾蚴病炎症的类固醇保留剂。

DOI：
10.1212/nxi.0000000000000606
发表时间：
2019
期刊：
Neurology(R) neuroimmunology & neuroinflammation
影响因子：
0
作者：
Anand,Pria;Mukerji,ShibaniS;Thon,Jesse;Gunaratne,Shauna;Cho,TraceyA;Venna,Nagagopal
通讯作者：
Venna,Nagagopal

Eastern equine encephalitis and use of IV immunoglobulin therapy and high-dose steroids.