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

• 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
• 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

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.

项目总结

项目成果

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

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
• 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.

• DOI: 10.1212/nxi.0000000000000917
• 发表时间: 2021-01
• 期刊: Neurology(R) neuroimmunology & neuroinflammation
• 作者: Wilcox DR;Collens SI;Solomon IH;Mateen FJ;Mukerji SS
• 通讯作者: Mukerji SS