Pilot Project Awards

Grant Title:Pilot Study for the Obesity and Metabolic Complications Translational Team 
Team Members:  Nicola Abate; Manisha Chandalia; Luca Cicalese; Cristiana Rastellini; Elizabeth Reifsnider

Abstract.
Clinical measures of adipose tissue mass (BMI, waist circumference, waist-to-hip ratio) do not adequately explain the inter-individual and ethnic heterogeneity in complications related to obesity. There is a need to identify novel/universal markers of risk for the 2 major complications of obesity, type 2 diabetes (T2DM) and cardiovascular disease (CVD). This study will focus on the central question of “adipose tissue dysfunction” as mediator of metabolic complications of positive energy balance, independent of body fat content and distribution. We have chosen a multidisciplinary approach with development of 3 projects each with a specific aim related to our central questions. These projects will take advantage of unique expertise of different investigators of this team to perform detailed metabolic studies in patients with obesity and the MS, patients with T2DM who undergo pancreatic transplant and obese children in the community. The results of the proposed study will provide support to the novel approach of identifying adipose tissue dysfunction, rather than obesity and fat distribution, as predictor of T2DM and CVD across all ethnic groups, age and gender. We will obtain necessary preliminary data for future grant submission to support our central hypothesis and develop stronger interaction within and outside UTMB clinical investigators in the area of obesity and its complications.

 

Grant Title:   Multidisciplinary Translational Team in Severe Asthma
Team Members:  William Calhoun; Allan Brasier; Alex Kurosky; John Wiktorowicz; Bill Ameredes; Mohammad Jamaluddin; Bruce Luxon; Curig owen Prys-Picard

ABSTRACT
Asthma is inflammatory airway disease associated with variable airway obstruction and airway hyperresponsiveness to a variety of stimuli. The mainstay of asthma therapy, glucocorticoids delivered via the inhaled route, is safe, effective, and well-tolerated. Severe asthma [SA] is characterized by resistance to inhaled glucocorticoids, persistent airways obstruction, and increased rates of morbidity, mortality, and resource utilization. Based on invasive, and clinically inconvenient measures, the pathogenesis of severe, steroid resistant asthma appears to be distinct from that of non-severe asthma [NSA], having less dependence on allergic mechanisms, greater body mass index, and qualitatively different inflammation (neutrophilic vs. eosinophilic). However, more broadly available measures, such as airway responsiveness to methacholine, and the putative surrogate marker of airway inflammation, exhaled nitric oxide (eNO), are not impressively different in SA compared to NSA {Moore 07}. Hence, there is an urgent need to develop tools to characterize asthma patients – to develop a molecular phenotype by which therapeutic responses can be prospectively distinguished. The goals of this pilot project are 1) to discover and validate prospectively peptide and protein biomarkers that predict the clinical phenotype of severe asthma, 2) to test the predictive ability of peptide and protein biomarkers to identify steroid resistance in asthma patients with and without severe asthma, and 3) to extend the application of protein biomarkers from invasive specimens (i.e. bronchoalveolar lavage fluid - BAL) to non-invasive specimens (e.g. exhaled breath condensates), an extension which would significantly expand the clinical utility of such biomarkers.

 

Grant Title:   ICTSA Multidisciplinary Translational Team Pilot Project in Hepatocellular Carcinoma Biomarker Identification
Team Members:   Cornelis Elferink; John Peterson; Ned Snyder; Heidi Spratt; Heidi Weiss; Kevin Rosenblatt; Steven Weinman; Orhan Ozkan Luca Cicalese

Abstract
20,000 new cases of hepatocellular carcinoma (HCC) are diagnosed each year, mostly due to chronic hepatitis C virus (HCV) infection. HCC is usually fatal and the poor prognosis is primarily due HCC normally being diagnosed at a late stage making successful therapeutic intervention difficult, if not impossible. In contrast, early detection of HCC provides a number of potentially curative treatment options. Unfortunately, existing screening strategies to detect HCC in its early stages lack both sensitivity and accuracy, and can be risky and expensive. Therefore, surveillance of patients at highest risk for developing HCC will benefit from serum biomarkers capable of accurately detecting HCC in its earliest stages. An ongoing collaborative interaction amongst several scientists and clinicians at UTMB seeks to identify potential biomarkers for HCC using sera from HCV-positive patients presenting with fibrotic liver disease (pre-HCC) or HCC. To date, biostatistical and bioinformatic analyses have identified quantitative differences in the serum peptide spectra that comprise panels of classifiers capable of discriminating between pre-HCC and HCC patient sera. Significantly, preliminary clinical findings suggest that two biomarker panels are capable of early HCC detection, and could also distinguish a HCC patient who had received an orthotopic liver transplant that restored normal liver function. The objective of this proposal is to identify the serum-borne peptides using strategies based on matrix-assisted laser  desorption/ionization time-of-flight and 18O stable isotope labeling (Aim 1), and to begin archiving new samples in preparation for a longitudinal biomarker validation study (Aim 2).

 

Grant Title:    Genetic and environmental determinants of viral bronchiolitis
Team Members:  Roberto Garofalo; Allan Brasier; Antonella Casola; Dana Gallite-Esham

Abstract
Bronchiolitis, the major cause of hospitalization in the first year of life is primarily caused by respiratory syncytial virus (RSV) infections. Exposure to second hand tobacco smoke (SHTS) occurs in up to 60% of the infants with RSV bronchiolitis in the US, and different studies have suggested that SHTS is a risk factor for the development of severe RSV infection. Oxidative stress response in the airways plays a major role in the pathogenesis of severe RSV bronchiolitis particularly if the process is enhanced by the exposure to prooxidative toxicants such as tobacco smoke. We have recently discovered that RSV potently inhibits the expression of antioxidant genes in epithelial cells. We hypothesize that combination of SHTS-induced reactive oxygen species (ROS) and virus-mediated inhibition of antioxidant enzymes leads to severe manifestations of bronchiolitis. Moreover, we hypothesize that the effect of SHTS on severity of RSV infection is linked to certain GST genotypes, such as the GST M1 null genotype which are associated with a complete lack of the enzyme. In this pilot project we will obtain nasopharyngeal secretions (NPS) from infants during the acute phase of naturally-acquired RSV infection. GST genotypes will be performed from NPS cell DNA. NPS samples will be tested for a panel of oxidative stress markers and cytokines which are associated with innate and inflammatory responses. To assess exposure to SHTS, levels of cotinine will be measured in urine of RSV-infected infants. Overall, these studies may lead to the identification of novel biomarker predictors of respiratory infection progression and disease severity and to the design of antioxidative pharmacologic interventions for the treatment of viral respiratory infections.

 

Grant Title:   Outcome Predictors in Severe Burn Injury
Team Members:   David Herndon; Marc Jeschke; Bruce Luxon; Allan Brasier; Celeste Finnerty; Heidi Spratt; Hyunsu Ju; Gabriela Kulp

 Abstract
A severe burn injury induces marked hypermetabolic and inflammatory responses effectuating dramatic protein degradation that compromises the function of multiple organ systems. Impaired organ function frequently results in multi-organ failure (MOF), the leading cause of mortality in burn patients. Although we can diagnose a burned patient in MOF, no reliable predictors or biomarkers have been found to determine which burn patients are at risk. Identification of accurate biomarkers for susceptibility to MOF would greatly improve burn patient treatment and outcome by allowing individualized treatment. Early identification of patients with a high probability of developing MOF would indicate that normal preventative treatment is not sufficient and that the patient would instead require aggressive prophylactic measures to decrease the likelihood of developing and succumbing to MOF. To date, all studies using conventional techniques have unsuccessfully focused on using the expression of single proteins to predict outcome. We hypothesize that severely burned patients at risk of dying from MOF have distinct proteomic and genomic profiles that, once identified, will allow us to identify the at-risk patients. Our hypothesis will be tested in two specific aims. In specific aim 1, we will apply classification methods to our set of microarrays to identify genomic expression patterns in white blood cells that are associated with mortality and MOF. In specific aim 2, we will apply quantitative differential proteomics to archived serum to identify patterns of protein expression that are associated with mortality and MOF. Statistical modeling will identify expression patterns and profiles that correlate with the main outcome trajectories MOF and death.

 

 Grant Title:    Muscle Aging and Sarcopenia        
Team Members:  Elena Volpi; Micah Drummond; James Goodwin; Glenn Ostir; Ken Ottenbacher; Doug Paddon-Jones; Elizabeth Protas

 

Abstract
Loss of lean body mass and decreasing muscle strength (sarcopenia) are significant contributing factors to decline in function and loss of independence in older adults. We have developed a comprehensive understanding of the role of essential amino acids and physical activity in muscle metabolism and protein synthesis in healthy older adults.  Our research team is now ready to begin translating these findings by developing and testing interventions in clinical geriatric populations.   
The goal of this MTT is to identify novel biomarkers of loss of muscle mass and function and test interventions to improve function and independence in older adults.  Inactivity is probably one of the major contributors to sarcopenia contributing to functional loss in hospitalized older patients. Our hypothesis is that markers of skeletal muscle catabolism can be detected in blood. However, overlapping disease processes can be powerful confounders, thus, in our first study, we will begin the biomarker discovery process in a controlled experiment utilizing a well characterized model of inactivity-driven muscle loss: bed rest. In this pilot study we will address the following specific aims in middle-aged subjects studied before and at the end of one week of bed rest with or without intensive rehabilitation:

1. To identify tissue molecular, metabolic and functional outcome measures associated with muscle loss during inactivity
2. To identify blood biomarkers that correlate with the tissue molecular, metabolic and functional measures of muscle loss

The results of this study will allow us to discovery potential biomarkers of sarcopenia and functional loss and subsequently extend our findings to selected patient populations.