Professor, Pharmacology and Experimental Neuroscience
Senior Associate Dean, UNMC Research and Development
University of Nebraska Medical Center
Durham Research Center 3008
985800 Nebraska Medical Center
Omaha, NE 68198-5800
Keywords: SIV, HIV, NeuroAIDS, Methamphetamine, CNS Dysfunction
KVNO News March 3, 2017
Friday Faculty Focus: Howard Fox
UNMC Newsroom | October 24, 2016
$20 million research grant is largest ever for UNMC
JAMA | July 12, 2016
Men With HIV Age Faster According to DNA Methylation Study
KIOS 91.5 FM | May 16, 2016
New study suggest link between HIV and premature aging
ABC News | April 21, 2016
Cells Appear to Age Faster in People With HIV, Study Finds
UNMC Newsroom | April 21, 2016
Measuring changes that link HIV, premature aging
In his own words - listen to Dr. Fox discuss careers in science and his research.
The brain is a unique organ, not only functionally but also in terms of host response to events such as damage and infection. We study processes in which this response leads to neurodegeneration and brain dysfunction. Much of our recent work has focused on biomarkers, which are objectively measured markers that correlate with disease states. They are useful for predicting risk of disease, development of disease, response to therapy, and other medical indications. Furthermore, they can give important clues to pathogenic mechanisms leading to means to prevent and treat disease. There is a distinct lack of such biomarkers in neurodegenerative diseases, representing a significant gap in our biomedical knowledge.
Our primary work models the development of neurodegeneration leading to dementia utilizing a brain disease that results after a known stimulus, infection with HIV. Using infection of rhesus monkeys with simian immunodeficiency virus (SIV) as a model of neuroAIDS, we are studying the virology, immunology, pathology, neurobiology, and molecular basis of the resulting central nervous system (CNS) disease. Two recent examples of this work are given below.
First, using “omic” technologies, we have discovered novel biomarkers for CNS disease, leading to mechanistic insights into neurodegenerative processes. Among these is the finding of osteopontin as a marker for HIV induced dementia, as well as the correlation of increased expression of one of its receptors on monocytes, CD44v6, with SIV encephalitis. Mechanistically, we have found that osteopontin acts to increase macrophage accumulation within tissues, paralleling the increased macrophages in the brain that are responsible for HIV dementia.
Second, we have embarked on a novel project assessing whether metabolites in the cerebrospinal fluid (CSF) would be useful as candidate biomarkers. Indeed they are, and using a combination of metabolomic and transcriptomic profiling, we have identified multiple new CSF biomarkers, which led to the discovery of a distinct mechanism of SIV-induced CNS disease. This work is now expanding to encompass other CNS disorders and holds great promise in having significant basic and applied impact.
Third, the now chronic nature of HIV has led to a major advancement in AIDS care. While HIV infected individuals are living longer, damaging effects of HIV persist in the brain and may interact with other neurodegenerative disorders. Dr. Fox leads the Chronic HIV infection and Aging in NeuroAIDS Center (CHAIN). The Center is supported by NIH, NIMH P30 MH062261. The goal of the CHAIN Center is to provide the necessary leadership and backbone of support to continue the outstanding research on HIV/AIDS, aging and the central nervous system ongoing at the University of Nebraska Medical Center and throughout the nation. Experts in a number of fields direct the Cell-Tissue-Animal, Imaging, Omics, and Therapeutics cores, along with the Administrative and Developmental cores. Visit the CHAIN Center web site for more information.
Students and postdoctoral trainees can participate in a number of the projects in Dr. Fox’s laboratory. Those interested in molecular training can join projects involved in synthesizing the combined transcriptomic, proteomic, and metabolomic data to examine pathophysiological mechanisms of disease. Those with interests in virology, immunology and/or neuroscience can help us probe the immune response to infection within the brain, and assess its effect on neuronal function. While each trainee will have an independent project, the common themes involve several members of the group.
- Ivanisevic J, Stauch KL, Petrascheck M, Benton HP, Epstein AA, Fang M, Gorantla S, Tran M, Hoang L, Kurczy ME, Boska MD, Gendelman HE, Fox HS, Siuzdak G. Metabolic drift in the aging brain. Aging (Albany NY). 2016 May;8(5):1000-20. PMID: 27182841. PMCID: PMC4931850.
- Gross AM, Jaeger PA, Kreisberg JF, Licon K, Jepsen KL, Khosroheidari M, Morsey BM, Swindells S, Shen H, Ng CT, Flagg K, Chen D, Zhang K, Fox HS, Ideker T. Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA. Mol Cell. 2016 Apr 21;62(2):157-68. doi: 10.1016/j.molcel.2016.03.019. PMCID 27105112
- Stauch KL, Purnell PR, Fox HS. (2014). Quantitative Proteomics of Synaptic and Nonsynaptic Mitochondria: Insights for Synaptic Mitochondrial Vulnerability. J Proteome Research, 13(5):2620-36. PMID 24708184
- Haverland NA, Fox HS, Ciborowski P. (2014). Quantitative Proteomics by SWATH-MS Reveals Altered Expression of Nucleic Acid Binding and Regulatory Proteins in HIV-1-Infected Macrophages. J Proteome Research, 13: 2109-2119. PMID 24564501
- Becker KM, Heinrichs-Graham E, Fox HS, Robertson KR, Sandkovsky US, O’Neill J, Swindells S, Wilson TW. Decreased MEG beta oscillations in HIV-infected older adults during the resting-state. J Neurovirology, 19: 586-594. PMID 24297500
- Yelamanchili SV, Morsey B, Rennard DA, Harrison EB, Emanuel K, Bastola DK, and Fox HS (2014). The evolutionary young miR-1290 favors mitotic exit and differentiation of human neural progenitors through altering the cell cycle proteins. Cell Death and Disease, 5: e982. PMID 24407235
- Chaudhuri AD, Yelamanchili SV and Fox HS (2013). MicroRNA-142 Reduces Monoamine Oxidase A Expression and Activity in Neuronal Cells by Downregulating SIRT1. PLoS ONE, 8: e79579. PMID 24244526
- Villeneuve L, Tiede LM, Morsey B, Fox HS (2013). Quantitative proteomics reveals oxygen-dependent changes in neuronal mitochondria affecting function and sensitivity to rotenone. J Proteome Research, 12: 4599-4606. PMID 23971408
- Purnell PR, Fox HS (2013). Autophagy-mediated turnover of dynamin-related protein 1. BMC Neuroscience, 14: 86. PMID 23937156