Research Projects

OBS-Research Projects

  • Case Study 1 – COPD (Kuo) Chronic Obstructive Pulmonary Disease
    Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the US, accounts for one fifth of all hospitalizations in individuals over 75 years of age and is the third most common cause of early readmission among individuals older than 65 years. The prevalence of COPD increases with age. Older adults are at particularly high risk for developing COPD due to aging-associated changes in physiology and immune function. For every 10-year increase in age, the prevalence of COPD increases 2-fold. COPD morbidity and mortality vary substantially by region and sociodemographic factors. Patients with COPD experience a high degree of comorbid illness and are at particularly high risk for cardiovascular disease, including hypertension, heart failure, and coronary artery disease. Recently, we have developed an institution-wide COPD registry at UTMB. This data source - which includes clinical, demographic, physiologic, and immunologic information on COPD patients seen from 2006 through 2018 - will serve as a principal data source for industry- and investigator- initiated randomized clinical trials, pragmatic clinical trials, and comparative effectiveness studies. Dr. Kuo is currently using this registry to examine the extent to which use of inhaled long-acting bronchodilators and inhaled corticosteroids reduce the risk of COPD-related exacerbations, hospitalizations, and emergency department visits.
  • Case Study 2 – RSV (Garofalo) Respiratory Syncytial Virus

    Studies led by Dr. Roberto Garofalo focus on Respiratory syncytial virus (RSV), a single-stranded, negative-sense RNA virus of the Paramyxoviridae family which is the single most important cause of acute lower respiratory-tract infections (bronchiolitis and pneumonia) in children. Epidemiological studies have shown that exposure to environmental tobacco smoke (ETS), also known as second-hand tobacco (cigarette) smoke, is a risk factor for the development of severe RSV infections. The complex interplay between exposure to ETS and viruses is the context of respiratory diseases is not fully understood, but it likely involves alteration of innate immune responses and other yet to be defined natural host defenses. Recent evidence suggests that severity of RSV infection may be driven directly by high-level viral replication in terms of viral load and delayed viral clearance in the airways, which could be the result of an impaired antiviral host response. To address this important problem, Dr. Garofalo has established a cohort of infants with acute respiratory tract infection < 24 months of age presenting to the UTMB outpatient Pediatric clinics, the Pediatric Urgent Care or admitted at Children’s Hospital. This cohort enrolls every year ~ 150-200 patients. Samples of nasopharyngeal swabs and nasal wash are collected for the detection and quantification of multiple viral pathogens and for the measurement of antioxidant enzyme levels, inflammatory cytokines, and other mediators of inflammation by Bioplex and proteomics approaches. Students will assist with the analysis of the cytokine and proteomics data of recent cohorts.

  • Case Study 3 – Chagasic Cardiomyopathy (Garg)
    Trypanosoma cruzi (Tc) is the causative agent for chagasic cardiomyopathy (CCM), to which 120 million people are exposed yearly in Latin America. Vectorial transmission of Tc occurs in the Southern half of the US, and the more than 300,000 infected individuals living in the US can further increase transmission through blood or organ donation. Approximately 1/3 of infected individuals will develop tissue fibrosis, ventricular dilation and arrhythmia, leading to heart failure. Chagas disease presents a neglected pathology as no effective therapy is available for the treatment of infected patients, who suffer formidable health challenges resembling those faced by HIV/AIDS patients. Dr. Garg’s studies are focused on molecular tools for the diagnosis of at risk patients, and potential therapies for the management of more than 20 million infected individuals at risk of developing cardiomyopathy and heart failure. Dr. Garg has shown that Tc induced intracellular Ca+2 flux (required for parasite invasion) elicits mitochondrial loss of membrane potential, decreased adenosine triphosphate generation and increased mitochondrial reactive oxygen species and oxidative stress in cardiomyocytes and chagasic hearts. Yet, what signals mitochondrial dysfunction after control of acute infection and why this cannot be arrested to prevent continuous cardiac loss of energy and damage is unknown. Dr. Garg is currently testing how Tc induced mtROS/DNA adducts create a feedback cycle of PARP1 activation that constitutes a danger signal in CCM. Her group will work to dissect the mechanism by which PARP1 interacts with the mitochondrial DNA polymerase γ (POLG) replisome and affects mtDNA synthesis in the context of chronic CCM and demonstrate that PARP1 hypoenzymatic activity is protective in incidents of heart failure in CCM. These studies will provide insights into PARP1’s role in disturbing mitochondrial integrity and provide the first indication of PARP1 being a genetic determinant in CCM outcomes.
  • Case Study 4 – Diabetes and Heart Disease (Martinez)
    Recent advancements in RNA-sequencing and computational algorithms to analyze genome wide transcriptome changes reveal that cardiac gene expression is extensively regulated via alternative splicing (AS). AS is tightly controlled during normal heart development and is dysregulated in both congenital and adult heart diseases by mechanisms largely unknown. Identification of AS regulators is important for understanding normal heart development and pathogenic mechanisms in human heart diseases. Therefore, this project focuses on AS regulator RNA Binding Fox-1 Homolog 2 (RBFOX2), which is strongly associated with both congenital and adult heart diseases. Dr. Martinez’s compelling results indicate that RBFOX2 splicing function is disrupted by a dominant negative isoform of RBFOX2 in diabetic hearts leading to aberrant expression of fetal AS variants. Her preliminary results suggest that RBFOX2 splicing activity is controlled via its dominant negative isoform in the developing heart and this regulation is reiterated in adult diabetic hearts. It is unclear how dominant negative RBFOX2 is generated and regulated in the developing heart and how it is dysregulated in the diabetic heart. In this project, mechanisms that control expression of dominant negative RBFOX2 in the developing heart will be determined and novel tools such as splicing switching oligonucleotides and blocking peptides will be generated to prevent dominant negative RBFOX2 activity in diabetic hearts. Results from these studies will lay the foundation for the development of novel therapeutics to restore RBFOX2 splicing function in human heart diseases.
  • Case Study 5 – Mtb/HIV (Endsley)
    Opportunistic infections such as Mycobacterium tuberculosis (Mtb) occur much more frequently in people with HIV (PWH) including after introduction of anti-retroviral therapy. Similarly, the presence of chronic infections such as Mtb or other co-infections or co-morbidities can promote HIV replication through mechanisms involving inflammation. The effects of inflammation in important tissue sites that host HIV reservoir cells is especially poorly understood. In this study, we will use archived specimens from human autopsy and from humanized mice infected with HIV and Mtb. The tissues of various organs, especially those associated with poor anti-retroviral penetration (e.g. adipose), will be mapped using molecular virology and multispectral imaging techniques to identify the cellular and tissue sources of HIV reservoirs and relationship with inflammatory outcomes. Bioinformatic approaches and follow up validation to identify novel pathways would also be performed.
  • Case Study 6 – Arborviruses (Vasilikas)
    In recent decades, Central and South America have experienced spillover of endemic arthropod-borne viruses (arboviruses) from wildlife reservoirs into humans, exchange and recombination of emerging arboviruses within the region, resurgence of arboviruses previously controlled by vaccination or vector control, introduction and spread of novel arboviruses, and exportation of viruses to other regions. Furthermore, there is great concern that newly-introduced Zika virus may spill back into an enzootic transmission cycle in the Americas. Increases in the rates of global travel, invasion of novel vector species, urban expansion, deforestation, and global climate change all elevate the risk of further arbovirus emergence, as does the breakdown of public health structures in Venezuela. The Coordinating Research on Emerging Arboviral Threats Encompassing the Neotropics (CREATE- NEO) project will provide a network of surveillance sites in the neotropics coupled to cutting-edge modeling approaches in order to anticipate and counter emerging arboviruses. We will identify novel and known arboviruses as well as the host-vector networks that sustain transmission of these viruses within the neotropics, map the spatial distribution of these transmission networks, and characterize virus transmission dynamics within these networks. These data will then be analyzed using niche modeling, machine learning to predict undiscovered hosts and vectors, and dynamical transmission models. We will also examine prospective and retrospective analysis of human infection and disease. To do so, we will leverage ongoing human clinical cohorts at multiple sites in Brazil and Panama. We will also develop novel diagnostics to capture known and novel arboviruses and model the impact of human and non-human primate movement on spillover and spillback of target arboviruses.
  • Case Study 7 – Vaccine Development (Chopra)
    The 2017-18 plague outbreak in Madagascar with ~2400 cases (>75% pneumonic) and ~9% causalities has led WHO (April 2018) to intensify the need for developing new generation subunit and live-attenuated plague vaccines. This need is exemplified by deadly plague cases in China (2019) and Congo (2020 with a 35% fatality rate). Y. pestis’ (Yp) ability to persist in dead hosts to resurge after years of silence, existence of antibiotic-resistant strains that occur naturally or have been intentionally developed, and no FDA-approved plague vaccine, is fearsome. Since the cellular immunity is also critical for protection, we focus first on identifying new virulence genes of Yp and then to delete them in combination to develop novel live-attenuated vaccine (LAV) strains. Immunological characterization of these mutants and their testing in higher animals, such as cynomolgus macaques (CM) and AGM, will provide a rationale for future clinical studies. There is a precedent for using a LAV against plague (EV76 strain) in humans. We plan to demonstrate efficacy and immune responses of two vaccine candidates generated from Yp CO92 (biovar Orientalis) against other Yp biovars (Antiqua and Medievalis), the F1-minus mutant of CO92, and Yp CO92 with LcrV variants, in bubonic and pneumonic mouse models. We will study the mechanistic basis of this protection by using mice, which lack Th17 cells, as well as IFN-γ and IgA k/o mice, to discern their links to neutrophil recruitment and mucosal immunity, to combat Yp infection in bubonic/pneumonic plague models. These innovative mechanistic/translational approaches will result in effective new generation plague vaccines. These studies require extensive statistical analysis, which would form an excellent platform for this grant and to train students.
  • Case Study 8 – Encephalitic Flaviviruses  (Beasley)
    Immunogenicity and efficacy of candidate subunit nanofiber hydrogel vaccines for encephalitic flaviviruses and control vaccines will be compared in mouse models of lethal, neuroinvasive disease following West Nile virus or Japanese encephalitis virus challenge.  Typical study endpoints will be induction of total antibodies (measured by ELISA) and neutralizing antibodies (measured by plaque reduction neutralization test) following one or two vaccine doses, and differences in survival rate and mean time to death following virus challenge.  Data from other studies using larger animal models with additional endpoints, including clinical chemistry and hematology parameters, can be made available for review and analysis.