Department of Neuroscience, Cell Biology, & Anatomy
Research Bldg. 17, 5.212D
Route: 1069 |
Tel: (409) 772-7705 | email@example.com
Lab Website: https://eugeninlab.com/
Education and Training
Universidad Austral de Chile, Valdivia, Chile. BS, 1996 (Biochemistry)
Pontificia Universidad Catolica de Chile, Santiago, Chile. PhD 2001 (Physiology)
PhD Thesis, Bonn University, Germany and Pontificia Universidad Catolica de Chile, Santiago, Chile. 2001 (Physiology)
The Albert Einstein College of Medicine, Bronx, NY, USA. Department of Pathology. (Postdoctoral training).
Currently the laboratory is focused on 4 interconnected areas of research
1. The role of cellular communication through gap junctions, tunneling nanotubes, hemichannels and ATP receptors during the pathogenesis of NeuroHIV.
Human immunodeficiency virus (HIV) infection of the central nervous system (CNS) can result in neurologic dysfunction with devastating consequences in a significant number of individuals with acquired immunodeficiency syndrome (AIDS).
Our focus is to examine the role of HIV infection of astrocytes in the pathogenesis of NeuroHIV as well as in immune cells, macrophages and T cells, with special emphasis in the role of gap junction channels, hemichannels of pannexins and connexin, ATP receptors and a new system of communication named tunneling nanotube (TNT). We examined how these systems amplify inflammation and toxicity and how these communication systems are altered by HIV infection in vitro and in vivo. These studies are essential to understand the mechanism by which HIV remains in the brain, as a reservoir of the virus, and to explore the question of how HIV changes the phenotype of HIV-infected cells to its advantage.
2. Identification of brain Biomarkers of dementia
Aging-related diseases including different kinds of dementia or cognitive impairment due to Alzheimer, Parkinson, multiple sclerosis (MS), stroke, or human immunodeficiency virus (HIV) are major public health problems. Despite the efforts and investment into new treatments and to understand the mechanisms of central nervous system (CNS) disease, the cellular and molecular basis of HIV CNS dysfunction is still poorly understood. Only recently, our group identified pannexin-1 channels as a key protein mediating CNS disease. Pannexin-1 channels are unique large ionic channels that allow the exchange of large signaling molecules between the cytoplasm and the extracellular space, including ATP and prostaglandins. Under physiological conditions, pannexin-1 channels are in a closed state that impedes intracellular ATP release and subsequent activation of ATP receptors. Only in pathogenic conditions such as ischemia/reperfusion, stroke, MS, and HIV these channels become open to further enhance inflammation and damage. Thus, pannexin-1 channels are unique pharmacological targets to reduce/prevent the devastating consequences of CNS diseases. Furthermore, our preliminary data indicate that the opening of pannexin-1 channels results in the secretion of several inflammatory factors that could affect the brain, including ATP and PGE2. Thus, serum concentration of ATP may serve as a biomarker of cognitive impairment in several CNS diseases. Interestingly, we found that specific pannexin-1 polymorphisms in different ethnic groups are associated with their differential susceptibility to CNS disease. Together, these observations have led us to formulate the hypothesis that pannexin-1 channels and the product released upon opening of the channel facilitate CNS disease in a range of CNS diseases. We truly believe that our unique interdisciplinary approach will help develop alternative therapeutic interventions to reduce the devastating consequences of Alzheimer, Parkinson, MS, stroke, or HIV.
3. Glioblastoma, a novel approach to cure this disease
Glioblastoma (GB) is one of the most aggressive and treatment-resistant forms of cancer. 5-year overall survival of GB patients remains at or below 5% and has not improved significantly in the past few decades despite advances in chemotherapeutic treatment and molecular diagnostics. Despite standard-of-care treatment encompassing maximal safe resection, adjuvant chemoradiation and chemotherapy with the alkylating agent temozolomide, GB is nearly certain to recur. Improved understanding of the underlying molecular and cellular biology will be crucial to designing more rational strategies for effective treatment.
Intercellular communication, a process that is critical to cancer cell development, invasion, and metabolism, has been identified as a potential mechanism of adaptation and stress response in GB. Discovery and characterization of long cytoplasmic bridge-like extensions connecting distant cells called tunneling nanotubes (TNTs) and tumor microtubes (TMs) (cytoplasmic projections connecting cancer cells in vitro and in vivo) have produced new evidence that these cellular protrusions promote invasive capacity and development of resistance to treatment in GB. The study of TNTs and TMs (referred to herewith as tumor membrane tubes, or TTs) is a rapidly growing field of cell biology, with strong potential to explain how the effects of vital cellular cargo, including organelles such as mitochondria, lysosomes, and others that play a role in cancer metabolism, can be amplified in vivo. Confocal imaging has detected TTs in human tumors following surgical resection, supporting theirs in vivo relevance in many invasive forms of cancer. Examination of intercellular communication occurring via TTs in an in vivo orthotopic animal model of GB has opened a new avenue for investigation of intercellular transfer of organelles in cancer in general, and especially in this form of cancer.
We have determined that TNTs are universally upregulated in tumor cells when subjected to physiologic or metabolic stressors, a consistent phenomenon in vitro and in vivo across many cancer types. Our collective preliminary and published data strongly support bi-directional intercellular exchange of mitochondria and lysosomes between cancer cells, including TNT-mediated mitochondrial transport between GB cells in vivo, and also between GB cells and normal astrocytes or mesenchymal cells. Downstream effects of this exchange include increased motility and invasive capacity of recipient cells. We hypothesize that TNT plays a key role in the susceptibility to GB and chemo/radioresistance. TNTs are a novel system that GB cells exploit by harnessing intercellular communication to thrive and survive in response to physiologic and metabolic stress. We propose the following three Aims to investigate the role of TTs in inter-organelle communication in cancer: Thus, targeting TNT could be a new mechanism to target GB and to cure this disease.
4. Heart disease and cell to cell communication
In recent years the life expectancy of human immunodeficiency virus (HIV) infected individuals has dramatically increased due to antiretroviral therapies (ART). However, while ART successfully controls viral replication, a significant number of HIV infected individuals display accelerated symptoms of aging-related diseases, such as cardiovascular disease. Because HIV does not productively infect the heart itself, this is thought to be due to indirect effects of HIV and ART on heart tissue. However, the mechanisms that mediate HIV cardiotoxicity are still very poorly understood. Based on our preliminary studies, we propose that HIV and its proteins target connexin43 (Cx43) containing channels – gap junctions (GJ) and unopposed hemichannels (uHC) – to elicit and spread metabolic/electrical dysfunction and inflammation in cardiomyocytes.
GJs are formed by docking of two uHC on the surfaces of contacting cells and serve to connect the cytoplasm of these cells. GJ facilitate cell-cell communication, including electrical, metabolic and calcium waves required for efficient cardiac muscle contraction. Our laboratory recently demonstrated that undocked uHC connect the cytoplasm with the extracellular space and facilitate the release of intracellular inflammatory factors. Both GJ and uHC enable the diffusion of molecules up to 1.2 kDa, including second messengers, ions, ATP, prostaglandins, small peptides and RNA. Cx43, a major component of both GJ and uHC, is abundantly expressed in the heart, and defects in Cx43 expression or localization are associated with arrhythmias, sudden death, cardiac malformation and heart attacks. Interestingly, we recently obtained evidence indicating that HIV infection alters Cx43 expression, localization, and channel function. We also found that HIV-tat binds directly to Cx43 promoter, potentially mediating Cx43 expression and function changes. HIV infection also promoted the opening of uHC, allowing the release of pro-inflammatory molecules, such as ATP and PGE2, into the extracellular environment. Consistent with increased uHC opening, we observed high circulating levels of these factors in all HIV infected individuals irrespective of ART and immune reconstitution. We also discovered that hearts obtained from HIV infected individuals had altered Cx43 localization: in HIV infected heart tissue Cx43 was not localized normally at the intercalated disks but instead had a lateralized distribution often associated with heart disease. All areas with compromised Cx43 localization showed signs of calcium overload, mitochondrial dysfunction, and muscle compromise which were independent of viral replication, immune reconstitution or comorbidities. Based on these results we have formulated the hypothesis that “HIV and its proteins upregulate Cx43 expression and alter Cx43 localization in cardiomyocytes, compromising the formation of intercalated disks, calcium coordination and electrical conduction, contributing to cardiovascular disease”. The proposed studies will elucidate the mechanisms of heart damage operating in HIV-infected individuals during the current antiretroviral era and may guide therapies designed to reduce the devastating consequences of heart disease in the HIV infected population.
1. Eugenin E.A. and Berman J.W. (2007) Gap junctions mediate HIV-bystander killing in astrocytes. J. Neuroscience. 27 (47): 12844-50.
2. Eugenin E.A., Clements J.E, Zink M.C., and Berman J.W. (2011) HIV infection of human astrocytes disrupts blood brain barrier integrity by a gap junction dependent mechanism. The Journal of Neuroscience.31(26):9456-65.
3. Hazleton J.E., Berman J.W. and Eugenin E.A. (2012) Purinergic Receptors are required for HIV-1 Infection of Primary Human Macrophages. J. Immunology. 188(9):4488-95.
4. Orellana JA., Williams D.W., Saez J.C., Berman J.W., and Eugenin E.A. (2013) Pannexin1 hemichannels are critical for HIV infection of human primary CD4+ T lymphocytes. J Leukocyte Biology. 94(3):399-407.
5. Eugenin E.A. and Berman J.W. (2014) Cytochrome C dysregulation induced by HIV infection of astrocytes results in bystander apoptosis of uninfected astrocytes by an IP3 and Calcium dependent mechanism. J Neurochemistry, 127 (5): 644-51.
7. Mishra BB, Lovewell RR, Olive AJ, Zhang G, Wang W, Eugenin E, Smith CM, Phuah JY, Long JE, Dubuke ML, Palace SG, Goguen JD, Baker RE, Nambi S, Mishra R, Booty MG, Baer CE, Shaffer SA, Dartois V, McCormick BA, Chen X, Sassetti CM. (2017) Nitric oxide prevents a pathogen-permissive granulocytic inflammation during tuberculosis. Nat Microbiol. 15;2:17072. doi: 10.1038/nmicrobiol.2017.72. PMID: 28504669
8. Okafo G, Prevedel L, Eugenin E. (2017) Tunneling nanotubes (TNT) mediate long-range gap junctional communication: Implications for HIV cell to cell spread. Sci Rep. 7(1):16660. doi: 10.1038/s41598-017-16600-1.
Link to Pubmed Publications
Link to Research Gate