UTMB Summer Institute in Biostatistics and Data Science Program Components

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.

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.

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.

Sodium glucose co-transporter -2 inhibitors (SGLT-2i) comprise a group of medications initially approved for management of hyperglycemia in individuals with type 2 diabetes. However, given evidence of improved outcomes in heart failure and observed benefits on delaying the progression of kidney disease, their approval has expanded to cover heart failure and chronic kidney disease in the absence of diabetes. One of the adverse events related to the use of SGLT-2i is the development of diabetic ketoacidosis (DKA), an acute and potentially life-threatening complication of diabetes. DKA is usually seen in individuals with type 1 diabetes who are unable to make their own insulin and are prone to develop DKA in situations of acute stress, prolonged fasting and/or missed insulin doses. Current practice in most hospitals is to hold SGLT-2i in all patients regardless of diabetes status.  A major reason for this practice is that it is difficult to identify DKA from the use of SGLT-2i because the blood sugar levels are usually not elevated as in classical DKA, hence the term euglycemic DKA (euDKA). However, evidence in support of the practice of holding SGLT-2i in hospitalized patients is scant and controversial. The goal of this project is to determine, using a large database with individual-level electronic medical record data, the frequency of euDKA among hospitalized patients who remain on the medication during their hospital stay when compared to those who discontinue, and to identify predictors for the development of euDKA. We will also explore the risk of hospital readmission due to heart failure in patients who stop the medication inpatient versus those who do not. These findings will inform current practice on the use of SGLT-2i  in the hospital setting.

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.

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.

The characteristics of our surroundings that we come in contact with on a daily basis can have profound effects on our health. These characteristics can include environmental factors related to where we live, such as air quality and the number of trees in our neighborhood. These characteristics can also include social factors, such as our socioeconomic status and the relationships we have with people around us. Dr. Downer’s research uses publicly available data to study how these environmental and social factors can influence people’s cognitive, physical, and mental health as they age. Students who work with Dr. Downer gain hands-on experience developing research questions, identifying publicly available data, performing data analyses, and presenting results.

Only recently have neuroscientists been able to really see neural activity with behavior in real time using the technique of fiber photometry. Because this technique is relatively new, there is not a good consensus for data analysis, leaving the door open for innovation. Our project is investigating neuronal activity in the nucleus accumbens shell during frustration behavior. There are currently no pharmacotherapeutics designed specifically to treat frustrative nonreward (FN). This is due, in part, to a lack of appropriate animal behavior paradigms suitable for screening therapeutics. While rats cannot experience frustration through the intricate cortical lens through which humans interpret frustration, there is every indication that rats have the same corticolimbic responses to FN as humans, and to be translationally useful, novel animal paradigms need to engage the specific neurocircuitry engaged in human FN. We have developed a non-invasive rat behavioral task based on the human Point Subtraction Aggression Paradigm that can quantify behavior (barpress durations) related to FN. This project will assess coherence of this novel rat task with circuit engagement of the human task. Our overall hypothesis is that our optimized FN task will engage the neurocircuitry for reward and FN similar to human FN and thus will be useful for screening of novel targets.

Every year more than one million people in the United States are burned, and ~480,000 cases receive direct medical care. The cost is high both financially and personally to the survivor. The annual cost of treating burns in the U.S. is estimated to exceed ten billion dollars. Of those who survive, 60 to 90% will develop hypertrophic scars. These scars result from excessive collagen deposition and are painful, itchy, and can impair function for decades. Improved initial burn treatment has extended the lives of those whose injuries were previously fatal, thus strategies to reduce the impact of scarring on physical and psychosocial outcomes and health-related quality of life are a priority for patients and clinicians. Burn scars severely limit participation in everyday activities (e.g., work, school, play, self-care), cause unhappiness with appearance, and interfere with sleep for decades after injury. As a result, quality of life can be poor. My research is focused on improving quality of life for the burn survivor, through translational studies that examine the impact of pharmacological and non-pharmacological interventions on scar and long-term outcomes. Students will lead projects that examine long term outcomes related to scarring and infection.

Induction immunosuppression, to minimize priming of the recipient immune system to initial antigen exposure, is a mainstay of kidney transplantation. The optimal agents and timing of immunosuppression remain debatable. There are currently no biologic data on how to predict or measure the response to induction immunosuppression. We aim to use a multi-omic approach to characterize the immunologic milieu of peripheral blood prior to allograft reperfusion. Based on prior experiments, we hypothesize differential changes in glucocorticoid responsiveness. We have collected peripheral blood at 2 intra-operative timepoints [(T¹) pre-immunosuppression, (T²) immediately pre-reperfusion] and performed targeted proteomic (TNF superfamily, BioPlex) and mRNA sequencing (RNA seq) analyses. Focus will be on proinflammatory plasma proteins and genes involving T-cell activity and glucocorticoid responsiveness.  Short- and medium-term graft function outcomes will be recorded. We anticipate actionable findings to include signals for differential glucocorticoid responsiveness, a well-documented phenomenon that is under-appreciated in transplantation. Peripheral blood gene expression data can provide context for interpreting plasma protein levels and may improve the ability to predict and measure the response to induction immunosuppression and adjust accordingly.