Multidisciplinary Translational Teams
1. MTT in Phenotypes of Severe Asthma
Investigators:
Principal investigator: W.J. Calhoun, MD, APICS
Co-investigators: M. Jamaluddin, PhD, J. Wiktorowitz, PhD, B. Luxon, PhD, A. Kurosky, PhD, A R Brasier, MD, B. Ameredes, PhD, H. Ju, PhD.
UTMB Departments: Medicine, Biochemistry and Molecular Biology
K12 Trainee: Curig Prys-Picard, MD, PhD, Division of APICS
Summary: Although patients with severe asthma constitute only 5-10% of all patients with the disease, this small subgroup accounts for a disproportionate share of morbidity and medical costs. Severe asthma is a syndrome that is characterized by a relative lack of responsiveness to gluocorticoids. It is clear that this group is heterogenous in nature, yet objective methods for identification of those at risk are not available. In this MTT, UTMB investigators will seek to identify protein patterns that are associated with asthma severity or its complications to improve the ability to phenotype subjects with asthma. This effort will involve interfaces with multicenter studies including the US Severe Asthma Research Program (SARP), Asthma Clinical Research Network (ACRN), and studies locally at UTMB.
Objectives/Milestones:
- Recruit normal volunteers to establish a reference dataset of normal BAL proteins;
- Create integrated clinical and proteomic database for severe asthma data management;
- Develop web based data capture forms for conducting clinical studies at UTMB and its clinics;
- Develop and validate a novel biomarker discovery platform for identification of proteomic signatures in bronchoalveolar lavage;
- Validate models for pattern recognition using cytokine patterns in an independent subject group;
- Compete for K-level NIH funding, and an NIH multi-investigator RO1 project.
CTSA Resource usage:
Bioinformatics, Translational Technologies, Biostatistics, Education
2. MTT in Burns Injury and Response
Investigators:
Principal investigator: David Herndon, MD
Co-investigators: M. Jeschke, MD, PhD, C. Finnerty, PhD, B. Luxon, PhD, H. Ju, PhD
UTMB Departments: Surgery, and Shriner Burns Hospital
K12 Trainee: C. Finnerty, PhD, Shriner Burns Hospital
Summary: The MTT in burns injury will address several translational aspects in burn injury/response. First, although significant improvements in burns management has resulted in a reduction in mortality to less than 10%, early identification of those at risk for multiorgan failure, or mortality is needed. Severe burns in humans produces a catabolic state that persists throughout the first year after burn. This state is mediated by an increase in catecholamine production, resulting in lipolysis, muscle wasting, reduced lean body mass and depressed immune response. Propranolol administration has been shown to reduce hypermetabolism, increase lean body mass and improve immune function. About 10% of patients doe not respond to propranolol for unknown reasons. In this MTT, ICTSA resources will allow the identification of multiorgan failure and mortality, enabling the UTMB Shriner Burns Hospital to be a site for a phase III multicenter trial in propranolol administration in burns outcome.
Objectives/Milestones:
- Data-mine an established integrated clinical, genomic and proteomic database for predictors of mortality and multiorgan failure in pediatric burn injury;
- Develop and validate these predictive models for multiorgan failure and mortality prospectively in an independent subject group;
- Identify proteomic and genomic predictors of propranolol response.
- Conduct high density sequencing of the beta adrenergic receptor to identify whether receptor genetic polymorphisms underly therapeutic resistance to propranolol.
- Compete for K-level funding for training, and be the central repository for the multi-center phase III translational study.
CTSA Resource usage:
Bioinformatics, Translational Technologies, Biostatistics, Education
3. MTT in Hepatitis C-Hepatocellular CA
Investigators:
Principal investigator: Stan Lemon, MD
Co-investigators: S. Weinmann, MD, PhD, J. Petersen, PhD, N. Snyder, MD, Jianli Dong, MD, H. Spratt, PhD, T. Wood, PhD, M. Evers, MD
UTMB Departments: Internal Medicine, Surgery Biochemistry and Molecular Biology, Pathology, and Institute for Human Infections and Immunity,
K25Trainee: H. Spratt, PhD
Summary: Chronic Hepatitis C infection is the most common cause of liver failure and hepatocellular CA (HCC) in the US. UTMB has significant strengths in Hepatitis C infections, and is the recipient U19 Hepatitis Cooperative Research Center (Stan Lemon, MD, PI) and a 5 year SPORE in GI Cancer (P50CA127004, BME, pending) . In the US, chronic hepatitis C infection is the most common predisposing factor for HCC. Early detection of HCC is important because surgical resection currently offers the best prognosis for long-term survival but unfortunately is possible in only 10-15% of cases, the remaining cases being too advanced for surgical intervention. For those without surgical intervention, median length of survival is measured in 3-6 months. Epidemiological studies have shown that a number of environmental and host factors modify the risk of HCC, such as ethanol use, gender and age, however accurate stratification of those at risk is not possible. Clinically, there are a paucity of biomarkers that indicate when high risk patients should undergo costly imaging studies. The goals of this MTT are to identify risk factors for HCC, identify prevalent HCV genotypes important in liver function in epidemiological
Objectives/Milestones:
- Conduct loss of heterozygosity analysis in matched HCC and adjacent normal tissue in subjects undergoing hepatic resection.
- Identify plasma biomarkers of HCC in patients with chronic Hepatitis C at a stage where tumors are surgically respectable.
- Serve as a training site for a newly funded K25 award in bioinformatics (H. Spratt, PhD).
CTSA Resource usage:
Bioinformatics, Translational Technologies, Biostatistics, Education
4. MTT in Pediatric Mucosal Infections
Investigators:
Principal investigators: Roberto Garofalo, MD, Tasnee Chonmaitree, MD
Co-investigators: Janak Patel, MD, Antonella Casola, MD, Thomas G. Wood, PhD, Alex Kurosky, PhD
UTMB Departments: Pediatrics, Biochemistry and Molecular Biology
K12 Trainee: Krystal Revai, MD, Antonieta Guerrero-Plata, PhD
Summary: Respiratory viruses are the most common cause of symptomatic human infections; their role is particularly important in children’s diseases. Respiratory syncytial virus, parainfluenza and other respiratory viruses cause upper and lower respiratory tract infection such as URI, pneumonia and bronchiolitis and play a significant role in pathogenesis of acute otitis media (AOM), the most common disease seen in pediatric practice. Active clinical/ translational research on viral infections in children has been longstanding in the UTMB Department of pediatrics.. The UTMB otitis media research group has pioneered studies of children related to the virologic aspect of AOM and viral-bacterial interactions. The present research project “Pathogenesis of virus-induced acute otitis media” (R01DC005841-Chonmaitree) is in its 6th year of funding and addressing the role of genetic polymorphisms and environment on AOM pathogenesis. The group also plans to study proteomic risk factors for AOM complicating URI.
Objectives/Milestones:
- Conduct a prospective study of 300 children with and without genetic polymorphisms (TNFa-308 and IL- 6-174) to determine the mechanisms by which genetic risk factors render the host otitis susceptible and whether environmental factors could modify OM risks in children with genetic predisposition.
- Investigate further the association between several other cytokine/ chemokine gene polymorphisms and otitis susceptibility using >800 archived DNA specimens.
- Define the unique patterns of protein expression in nasopharyngeal secretions that are associated with the risk of developing AOM following URI in children.
- Support junior faculty in the research group who is preparing for K grant submissions.
CTSA Resource usage:
Bioinformatics, Translational Technologies (genomics and proteomics), Biostatistics, Education and Training.
5. MTT in Obesity and its metabolic complications.
Investigators: N. Abate, M.D.; Ron Tilton, Ph.D.; M. Chandalia, M.D.; Liz Reifsnider, PhD; Elena Volpi, M.D.; Bernard Godley, M.D.; Massoud Motamedi, Ph.D.; Cristiana Rastellini, M.D.; Luca Cicalese, M.D.; Richard Johnston, MD.
UTMB Departments: Internal Medicine, Ophthalmology, Nursing, Surgery.
Trainee: Wendy Pan, M.D., Department of Medicine; Gibran Khurshid MBBS, Department of Ophthalmology.
Summary:
Obesity is considered the driving force behind the growing epidemic of type 2 diabetes and cardiovascular disease in the US population. Clinical efforts to identify patients with obesity that are at risk for developing type 2 diabetes and cardiovascular disease have lead to the definition of the Metabolic Syndrome in the NCEP ATP III guidelines, in 2002. However, only approximately 1/3 (25%) of the overweight/obese population develops the metabolic syndrome and only 1/3 (8%) of the metabolic syndrome patients develop type 2 diabetes with increased risk for cardiovascular disease. On the other hand, it has become apparent that persons with low BMI and even with low waist circumference may be at risk for developing diabetes and cardiovascular disease. The limitation of the current definition of the metabolic syndrome in identifying patients at risk is even more evident in ethnic minorities. For example, for any degree of obesity and fat distribution Asian and Hispanics appear to be more susceptible to type 2 diabetes when compared to Whites of European descent. This observation could be explained on the basis of ethnic diversity in adipose tissue function and its ability to provide metabolic balance in conditions of excessive caloric intake. Our MTT will focus on identification of metabolic and genetic markers of adipose tissue dysfunction that may predict susceptibility to type 2 diabetes and its complications across all ethnic groups, independently of fat mass and distribution. Study subjects will be identified in the UTMB outpatient service clinics. Biomarkers will be identified looking at adipose tissue microarrays and proteomic analysis of adipose tissue samples for the diabetes risk, and looking at proteomic analysis of urine specimens for the diabetic complications. Inflammatory biomarkers will be major, but not exclusive, candidate for evaluation. Once these biomarkers are identified, a series of clinical and mechanistic studies will study specific pathways that are involved in the pathogenesis of insulin resistance, beta-cell dysfunction and retinal/renal abnormalities of these patients. This work will include metabolic patient-oriented research and also studies in cell and animal models to confirm mechanistic relevance of findings in association studies. Since it has recently become evident that aggressive glycemic control increases risk for mortality in patients with type 2 diabetes, we will develop intervention studies using both medical and metabolic surgery approaches to accomplish resolution of adipose tissue dysfunction as preferable approach to prevent type 2 diabetes and its complications. Surgical intervention with whole pancreas or islet cell transplantation will be evaluated for its effectiveness in improving adipose tissue function and risk for progression of diabetes complications.
Objectives/Milestones:
- Identification of extreme phenotypes. We will identify the following extreme phenotypes for development of type 2 diabetes and its complications from UTMB clinics: 1. Patients over the age of 65 yrs with metabolic syndrome who have not yet developed type 2 diabetes; 2. Patients with the metabolic syndrome who have developed type 2 diabetes at age less than 40 years; 3. Patients who developed diabetes complications (renal and/or retinal) within 1 year from diagnosis, and 4) patients with type 2 diabetes for more than 30 years duration and never developed renal or retinal complications. All population ethnic groups will be included with equal representation.
- Identification of biomarkers. We will validate top 10 candidate biomarkers for diabetes and its complications present in adipose tissue and urine samples using microarrays in adipose tissue, immunological methods or mass spectrometry-based multiple reaction monitoring in adipose tissue and urinary samples.
- Pilot surgery studies. We will obtain preliminary data with metabolic surgery approach and transplantation of plancreas/islets approach for its effect on adipose tissue function.
- Data analysis. Use computational bioinformatics and statistics to integrate microarray and proteomic data into a comprehensive, hypothesis-generating model of the dysregulated metabolism leading to diabetes and its complications.
- Identification of novel hypotheses-study design. Identify mechanistic hypothesis to be tested in metabolic studies involving mechanisms of insulin resistance, beta-cell dysfunction and retina/kidney morbidities found in diabetes. Design cell models and animal models to test validity of mechanistic hypotheses generated from the microarray/proteomics data. Design therapeutic approaches to improve adipose tissue function, including surgery.
- Conduct a prospective observational study of the role in inflammation in metabolic complications in children with prediabetic conditions;
CTS Resource usage:
Translational Technologies, Bioinformatics, Education.
6. MTT in Aging Muscle and Sarcopenia
Investigators:
Principal Investigators: Elena Volpi, MD, PhD
Co-investigators: E. Borsheim, J. Goodwin, G. Ostir, K. Ottenbacher, D. Paddon-Jones, E. Protas, B. Rasmussen
UTMB Departments: Internal Medicine, Surgery, Physical Therapy, Rehabilitation Sciences
K12 trainee: M. Drummond, PhD
Summary:
Loss of lean body mass and decreasing muscle strength are significant contributing factors to decline in function and loss of independence in older adults. UTMB is recognized nationally for research related to muscle biology and protein metabolism. For the past nine years research on aging muscle has been conducted by investigators supported by an Older Americans Independence (Pepper) Center grant from the NIA (P30AG024832, J. Goodwin, PI) and a series or R01s (R01AG16738, K. Ottenbacher, PI; R01HD0518441 E. Protas, PI; R01AR049877, B. Rasmussen, PI; and R01AG018311, R03AG023215, E. Volpi, PI). We have developed a comprehensive understand of the role of essential amino acids and exercise 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 populations. Conducting trails in patient populations is a new area of investigation of the aging muscle research team and will require the assistance of the ICTSA cores and related resources.
The goal of this MTT is to develop and test interventions to improve function and independence in older adults.
Objectives/Milestones:
- Identify functional outcome measures sensitive to change in muscle function and related to improved independence in older adults;
- Develop sampling plans and recruitment strategies to obtain large samples of patients experiencing acute hospitalization and at risk for loss of independence;
- Establish protocols and designs to conduct rigorous clinical trails using hospitalized patients and older persons living in the community.
- Train doctoral students, postdoctoral fellows and K12 trainees in the data collection and analysis methods appropriate for conducting clinical trails in older adults.
CTSA Resource usage:
Clinical Trails Office, Study Coordinators, Biostatistics, Education
7. ARBOVIRAL VACCINE DEVELOPMENT
Investigators: Alan Barrett, PhD, D. Mark Estes, Ph.D., Scott C. Weaver, Ph.D., Richard Rupp, M.D., Kwabena O. Sarpong, M.D., Jyotsna Pandya, Ph.D., and H. Spratt, PhD
Summary:
It is well–documented that the most effective modality for preventing infectious diseases is vaccination. The UTMB Sealy Center for Vaccine Development is a comprehensive vaccine center that develops and supports multidisciplinary programs in discovery, basic and applied research/preclinical development, clinical trials/clinical research, public policy research, community outreach, and education and training. In recent years arboviruses have become increasingly important by causing emerging infectious diseases (e.g. West Nile Virus) and as potential bioterrorist agents. The goal of this MTT is to support the various aspects of the vaccine development pathway, from preclinical development to clinical trials, towards bringing vaccines against arboviral diseases to the marketplace.
Objectives/Milestons are to:
- Develop candidate vaccines to prevent diseases caused by arboviruses;
- Identify correlates of protective immunity for vaccines against arboviral diseases
- Establish protocols and designs to conduct rigorous clinical trials in individuals living in the community;
- Train postdoctoral fellows and K12 fellows in the data collection and analysis methods appropriate for conducting clinical trials in children and adults and undertaking preclinical vaccine development.
8. REPRODUCTIVE WOMEN’S HEALTH
Investigators:
A. Berenson, MD, C. Radecki Breitkopf, PhD, D. Freeman, PhD, E. Reifsnider,PhD, WHNP, APRN, H. Wu, PhD, M. Gallagher, C. Ripsin, MS, MPH, MD, J. Temple, PhD and P. Van den Berg, PhD, MPH
Summary:
The reproductive period comprises 35 years of a woman’s life. During this time, women experience an evolving spectrum of physiological and psychosocial issues that may affect their health. UTMB is a leader in research on women’s health, including promotion and prevention, including pregnancy, contraception, skeletal health, and health risk behaviors. Our team’s research focuses on minority women of low socio-economic status, and has led to the development of several clinical interventions. We represent various schools, disciplines, and departments, highlighting our historical strengths in translational research among clinical and community populations. Our unique group has representation from obstetrics/gynecology, nursing, psychology, epidemiology, family medicine, and statistics. We are testing several new interventions. One is an educational and behavioral intervention designed to increase the consistency and correctness of oral contraceptive use among new users 16-24 years of age. Another intervention involves how nurses inform women that they have an abnormal Pap smear result. This culturally sensitive intervention is designed to increase the number of women who report to clinic for further evaluation after being informed of an abnormal Pap smear. New projects will include developing a weight loss intervention during the postpartum period and assessment of health risk behaviors among adolescent women. The broad goal of this MTT is to develop and test interventions to improve health outcomes in reproductive-aged women, which will influence their health status in later years.
Objectives/Milestones:
- Expand our knowledge base of the health needs, risk and protective factors, and culturally sensitive health interventions among underserved women, with a particular focus on Hispanics
- Conduct focus groups and qualitative surveys to investigate determinants of health behaviors among underserved women of reproductive age.
- Develop, pilot test, and refine a battery of measures that integrates objective physiological and psychosocial outcome data (e.g., assays of relevant biomarkers, bone density tests, blood pressure, self-report of social support, stress, depressive symptoms, and body image) that we will apply to a broad range of studies. For example, a study of more than 800 women using one of three contraceptive methods will measure bone mineral density, serum lipids, and depressive symptoms
- Test, adapt, or modify existing health behavior interventions to address significant barriers to and facilitators of healthy practices specific to our multiethnic population, and ensure sustainability of the interventions.
- Train T32 postdoctoral fellows, K12 scholars, and junior faculty in methods appropriate for conducting clinical research in multiethnic cohorts of reproductive-aged women
