LSU Biomedical Collaborative Research Program

2017-2018

Mechanisms of Premature Muscle Fatigue in Sedentary and Exercise Trained Adults

Brian Irving (LSU A&M) and Owen Carmichael (PBRC)

Habitual exercise enhances metabolic health, and in many cases improves chronic diseases, but few Americans meet established guidelines for exercise. Premature muscle fatigue is a key contributor to inadequate exercise attainment, but the metabolism of muscle fatigue, and its evolution with exercise training, is poorly understood.   Therefore, this project will measure key molecular determinants of muscle fatigue in sedentary adults before and after aerobic exercise training: acetyl-CoA buffer capacity, PDHa oxidation, and mitochondrial respiratory function.  Understanding the influence of these physiological processes on premature muscle fatigue in exercise-trained individuals is the first step toward personalized pharmacology and exercise regimens that decrease muscle fatigue and thereby increase the ability to reap health benefits of exercise. This project represents a unique opportunity to combine distinct capabilities in mitochondrial measurement, including in vivo magnetic resonance spectroscopy with 13C-labeled acetate at Pennington Biomedical and in situ high-resolution respirometry at the LSU main campus, to advance our understanding of premature muscle fatigue. The anticipated result of this effort is a characterization of oxidation rates and buffer capacities, which will lead to follow-up studies that manipulate these components via pharmacology in humans, or pharmacology or genetic manipulation in animal models.


Plastic Restoration of Neural Networks in Tinnitus

Charles Lee (LSU A&M) and Jason Middleton (LSUHSC-NO)

 Tinnitus, the phantom perception of non-existent sound, results partly from the deterioration of inhibitory neuronal circuits in the central auditory system. Chronic tinnitus is a major health issue, resulting in severe deficits in quality of life and lost productivity in all sectors of society. Our primary objectives in this collaborative proposal is to develop a therapeutic approach for restoring lost inhibitory neural circuit function in the auditory cortex that may underlie the increased neural excitation experienced during chronic tinnitus. Our central hypothesis is that chronic tinnitus results in a substantial deterioration of inhibitory neurons and lost efficacy of the remaining inhibitory synaptic connections to auditory cortical neurons, whose survival can be promoted via cell-type-specific plastic stimulation. Here, we plan to test a novel cell-type specific method for restoring normal function in these neurons. These results will have a positive impact by identifying and validating a novel therapeutic route towards alleviating tinnitus in human patients.


Siah2 in Liposarcomas

Elizabeth Floyd (PBRC) and Frank Lau (LSUHSC-NO)

The American Cancer Society estimates that 12,390 new cases of soft-tissue sarcoma will be diagnosed in 2017 alone, and 4,990 of those individuals will die of that same disease. Since the majority of soft tissue sarcomas are adipose tissue-derived liposarcomas (LPS), and enzymes of the ubiquitin–proteasome system are often dysregulated in tumor development, the general aim of this pilot and feasibility study is to determine if Siah2 (a mammalian homolog) expression is dysregulated in well-differentiated LPS (WDLS) and dedifferentiated LPS (DDLS). The investigators hypothesize that Siah2 expression is reduced in DDLS compared to WDLS and that reduced Siah2 activity inhibits differentiation in WDLS. This project aims to determine Siah2 mRNA and protein expression levels in LPS subtypes to test the hypothesis that Siah2 is differentially expressed, as well as to examine the effects of Siah2 inhibition.


Solid-State NMR Studies of the Dynamic Structure of Aspergillus Fumigatus Cell Walls

Tuo Wang (LSU A&M) and Ping Wang (LSUHSC-NO)

Invasive fungal infection often results in fatal diseases in individuals with immunodeficiency if left untreated. Existing antifungal drugs were mainly designed to target fungal cell membranes, but they also bind to cell membranes of humans, thus causing severe side effects. To guide the development of novel antifungals, we propose to employ solid-state NMR spectroscopy to investigate the cell wall structure of Aspergillus fumigatus, a major pathogenic fungus causing invasive aspergillosis. The investigators will assess the intermolecular packing between different carbohydrates and between carbohydrates and glycoproteins in intact and native fungal cells to reveal invaluable information on the dynamical profile and porosity of cell walls, and will also develop a solid-state NMR method to characterize unlabeled biosystems.


Spectroscopic Imaging Guided Cancer Surgery

Jian Xu (LSU A&M) and Philip Boudreaux (LSUHSC-NO)

The long-term goal of this proposal is to address limitations in removing cancerous tumors by designing imaging devices for intraoperative cancer diagnostics to help surgeons delineate tumor margins, to identify small residual and metastatic tumor nodules, and to determine if the tumor has been completely resected, in open and minimally invasive surgeries. The specific aims are (1) to develop and optimize a near-infrared (NIR) imaging system (spectroscopic device and camera) for sensitive cancer detection under open and minimally invasive conditions and (2) conduct a pilot clinical trial of pancreatic cancer surgery under spectroscopic guidance. Accomplishment of this trans-disciplinary project will have a significant impact on designing translational engineering devices for the intraoperative diagnosis in image-guided cancer surgery to “enhance health, lengthen life, and reduce illness” (NIH mission).


Three Dimensional Body Scanning for Biomedical Applications

Steven Heymsfield (PBRC) and Peter Wolenski (LSU A&M)

This project proposes to develop state-of-the-art algorithms and accompanying universal software that can be used on any 3D optical device for accurately quantifying body dimensions, shape, and composition. The developed modules will be validated with CA, DXA, and ADP in a sample of healthy adults. Novel shape indices for predicting health outcomes will be explored. The developed 3D system tools that dovetail with CA guidelines and that are capable of providing body composition and shape estimates will position us to be highly competitive for securing grant support from the NIH, NSF, and Department of Defense in areas we recognize these organizations will be emphasizing over the next several years.


Validation of Phase Contrast X-ray Imaging of Brown Adipose Tissue

Kenneth (Kip) Matthews (LSU A&M) and Jackie Stephens (PBRC)

Obesity is a major public health crisis with limited long-term effective treatments. Pharmacological agents that activate brown adipose tissue (BAT), or cause "beiging" of white fat, hold promise for promoting weight loss maintenance when paired with sustained reduction of energy intake. However, few tools are currently available for in situ localization and quantification of BAT activity. This project will demonstrate that X-ray grating interferometry/tomography is a viable tool to study BAT in rodent models in situ, by comparing to established biopsy-based methods such as mRNA and other biomarkers, as well as in vivo radiotracer imaging of mitochrondrial-related cell function.  This proposal performs the technology validation to demonstrate x-ray interferometry as a non-invasive imaging tool to study the role of BAT in obesity and next-generation obesity treatments

   

2016-2017

Bilateral Transfer of Motor Skills and Brain Activation Patterns: A First Step to Determine Whether Rehabilitation Protocols using Transfer Are Appropriate for Older Individuals

Arend Van Gemmert (LSU A&M) and Owen Carmichael (PBRC)

This project aims to produce data critical for success to develop and get externally funded a proposal addressing whether bilateral transfer of learning protocols developed using college aged adults applies to rehabilitative settings with older adults. Before it can be determined how to optimally maintain and restore motor skills in older adults, it needs to be determined what brain circuitry healthy young individuals recruit (using fMRI) when they perform known and learned motor tasks. This project satisfies this need and thus it establishes methods and preliminary data needed for future investigation into the viability of bilateral transfer of learning approaches in the elderly.

Computational Fluid Dynamics and Pediatric Airway Obstruction: Methodology and Potential Applications

Michael Dunham (LSUHSC-NO) and Keith Gonthier (LSU A&M) 

The proposed research will computationally examine airflow within the laryngotracheal airway of children. The investigators plan to construct three-dimensional patient specific airway models that will be subjected to high-fidelity computational fluid dynamics (CFD) evaluations under simulated physiologic conditions. Predictions will be used to identify, interpret, and catalog important aerodynamic parameters that characterize airflow efficiency and airway surface stress distributions, and to develop diagnostic and staging techniques for pediatric airway disease and surgical prototyping. Techniques developed during the project may be used to refine the computational analysis of upper respiratory airflow and extend its application in a clinical setting.

The Effect of Screen-Time Exposure and Sedentary Behavior on Preschool Children’s Fundamental Motor Skill Acquisition

Kip Webster (LSU A&M) and Amanda Staiano (PBRC)

Early interventions are critical in curbing the childhood obesity epidemic and setting children up for a healthy trajectory in life. In response to the critical need for effective obesity reduction interventions in young children, a new collaboration between Co-PI Elizabeth "Kip" Webster, PhD, Assistant Professor in the LSU School of Kinesiology, and Co-PI Amanda Staiano, PhD, Assistant Professor at Pennington Biomedical Research Center, has emerged that will unite each investigator’s expertise in preschool children’s fundamental motor skills (Webster) and early childhood obesity and sedentary behaviors (Staiano). The proposed project is an ancillary project that will add new assessments of fundamental motor skills to a parent study awarded to Dr. Staiano (parent funding from the National Institutes of Health, U54 MD 008602). The proposed project will collect feasibility and pilot data to position Drs. Webster and Staiano to be competitive for external funding, including specific calls by the National Institutes of Health (e.g. PAR-15-346 and PA-14-177).

The Role of Maternal Adipose Tissue in the Preeclamptic-like BPH/5 Mouse

Jennifer Sones (LSU A&M) and Leanne Redman (PBRC)

Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by a sudden rise in maternal blood pressure during the second half of gestation and is one of the leading causes of maternal and perinatal morbidity/mortality. There is no way to positively predict which pregnant women will develop PE; however, a number of maternal conditions have been labelled as risk factors, such as chronic hypertension, pre-gestational diabetes, and increased adiposity. To study the origins of PE, our laboratory utilizes BPH/5, an inbred genetic mouse that exhibits the cardinal signs of PE along with increased reproductive white adipose tissue (rWAT) deposition compared to control mice. Preliminary data in BPH/5 pregnant mice suggests calorie restriction and reduction of rWAT prevents adverse pregnancy outcomes in this model. The overarching aim of our proposal is to test the central hypothesis that maternal adiposity plays a key role in the development of PE-associated adverse pregnancy outcomes in BPH/5 mice with rWAT serving as a source of inflammatory signals to the maternal-fetal interface.

Role of Type 7 Adenylyl Cyclase in Innate Immunity

Masami Yoshimura (LSU A&M) and Guoshun Wang (LSUHSC-NO)

Our overarching hypothesis is that AC7 is a pivotal regulator in innate immunity, and is therefore a potential therapeutic target for immune diseases. This joint investigation aims to interrogate how AC7 loss-of-function in innate immune cells, such as macrophages and neutrophils, undermines their immune capacities. Completion of the proposed research will verify the role of AC7 in phagocytic host defense.

Virtual Reality Exposure Therapy for Post-Traumatic Stress Disorder in Civilian Gunshot Victims: A Design and Feasibility Trial

Erich Conrad (LSUHSC-NO), Jennifer Hughes (LSUHSC-NO) and Xin Shane Li (LSU A&M)

The proposed project would develop, standardize, and pilot test Virtual Reality Exposure Therapy (VRET) for post-traumatic stress disorder (PTSD) in gunshot victims. By investigating a novel intervention that draws on basic, specialized, and applied sciences, this study would promote a multidisciplinary, translational approach to clinical problem-solving. If our aims are achieved, we will be the first team to develop and test VRET to treat PTSD in gunshot victims.

 

2015-2016

Mechanisms of sigma66-RNAP: CT663-mediated transcriptional regulation

Megan Macnaughtan (LSU A&M) and Li Shen (LSUHSC-NO)

This project aims to explain the developmental cycle and virulence program in Chlamydia trachomatis (CT). Chlamydiae are medically and agriculturally important bacterial pathogens that cause a wide variety of diseases in humans and animals. In this application, Macnaughtan and Shen seek to define the functional and structural relationships of a protein complex containing an initiation factor (σ66), the core enzyme of RNA polymerase (RNAP), and the CT663 protein. This protein complex is important in the transcriptional machinery of CT. The proposed study will test the hypothesis that the functional and structural relationships of the protein complex impact transcription during the CT developmental cycle.

Novel MicroRNA based therapeutic approaches to suppress breast tumor growth using SPECT imaging

Michael Mathis (LSU A&M) and Suresh Alahari (LSUHSC-NO)

Previous work in Mathis’s and Alahari’s labs has identified a novel protein, Nischarin, which blocks tumor cell migration and invasion and can work as an inhibitory agent in breast cancer growth. This protein inhibits cell proliferation and cell invasion, which may explain its effect on tumor growth and metastasis. The objective of this study is to determine whether the suppression of specific RNAs (miR-27b and miR-23b) result in an increase of Nischarin and the robust inhibition of tumor growth. This will be observed in real time using single-photon emission computed tomography (SPECT) imaging. The proposed study will elucidate the significance of RNA suppression in breast cancer formation and validate its function as a novel therapeutic strategy for highly advanced breast cancers.

Cellular Scaffolds: A novel approach for the production of functional, implantable microvascular networks

Todd Monroe (LSU A&M), Dan Hayes (LSU A&M) and Frank Lau (LSUHSC-NO)

Tissue engineering has the potential to revolutionize medicine, but significant hurdles remain. Prominent among these is the ability to create functional, implantable microvascular networks (MVNs). Using biotechnology that allows cell sheets to be stacked, Monroe and Lau will create thick, multilayer cellular constructs with intact extracellular matrices and tight cellular junctions to form MVNs that are perfusable in vitro. These technologies are well developed, making this a highly feasible approach. In keeping with the NIH’s stated goal of encouraging collaborations between the life and physical sciences, this project will ensure that the entire production is undertaken with optimal consideration of both physical (channel design, fluid dynamics, perfusion methodology, etc.) and biological (cellular development, co-culture conditions, physiological considerations, etc.) aspects.

Cell traction force measurement to investigate tumor-suppressive function of Nischarin

Kidong Park (LSU A&M) and Suresh Alahari (LSUHSC-NO)

Nischarin is a newly discovered protein that suppresses cancer invasion and metastasis. In a recent study, Nischarin expression has been shown to be lower in breast cancer tissues, and additional decreases in Nischarin expression are observed in the breast cancer tissues of patients with lymph node metastasis. However, the effects of Nischarin on cellular mechanics and cancer invasion have not been fully investigated. During this project, the cell traction force (CTF) of breast cancer cells with different expression levels of Nischarin will be measured in various conditions to investigate how Nischarin regulates cell mechanics in cancer invasion. The proposed research will allow us to expand our understanding of how Nischarin regulates migration, motility, and invasiveness of the breast cancer cells and to develop a CTF measurement technique with clinical applications.

Cardio-pulmonary responses in mice following inhalation exposure to environmentally persistent free radicals

Arthur Penn (LSU A&M), Kurt Varner (LSUHSC-NO), Tammy Dugas (LSU A&M) and Alexandra Noel (LSUA&M)

Inhaled environmentally persistent free radicals (EPFRs)—a unique particle-pollutant system that forms during combustion processes—can penetrate deep into the lungs and move into the blood, potentially producing systemic and localized oxidant and inflammatory reactions. The project’s working hypothesis is that inhaled EPFRs at environmentally relevant concentrations will induce cardio-respiratory inflammation and oxidative stress responses, which will drive altered pulmonary, cardiac, and vascular functions in mice. The proposed experiments will use a new customized whole-body inhalation system the researchers have developed to examine the health impacts of “real world exposures” to inhaled EPFRs in mice. It is predicted that this new customized exposure system will model (in mice) human inhalation exposures to airborne particulates containing EPFRs.

Phenotypic and transcriptomic analyses of Vibrio cholerae colonial phase variants

Gregg Pettis (LSU A&M) and Christopher Taylor (LSUHSC-NO)

The bacterium Vibrio cholerae causes cholera, the devastating diarrheal disease that affects millions of people worldwide each year. V. cholerae produces an exopolysaccharide (Vibrio polysaccharide, VPS) that aids in formation of biofilms. VPS production and biofilm formation appear to be important for V. cholerae survival in aqueous systems and for its ability to establish infections. Strains of V. cholerae belonging to the O1 and O139 serogroups are responsible for the current cholera pandemic. Pettis and Taylor are interested in identifying the genes that are important for VPS production and biofilm formation in V. cholerae and have previously identified such genes in the O1 serogroup. In the proposed research, similar phenotypic and transcriptomic analyses will be performed on phase variants belonging to an O139 serogroup strain, as well as comparative analyses of the O1 and O139 transcriptomes.

GUMBOS, a new therapeutic approach for the prevention and treatment of gonorrhea

Isiah Warner (LSU A&M) and Jeffrey Hobden (LSUHSC-NO)

Neisseria gonorrhoeae is a sexually transmitted pathogen that infects over 820,000 Americans annually, with Louisiana ranking #1 per capita in new cases of gonorrhea. Complications of infection include pelvic inflammatory disease, infertility, arthritis, and an increased susceptibility to HIV/AIDS. An increasing concern is the development of multi-antibiotic resistant N. gonorrhoeae. In response to this global crisis, Warner and Hobden have developed a strategy for creating novel antimicrobial agents known as GUMBOS (Group of Uniform Materials Based on Organic Salts). The objective for this project is to synthesize and test new and existing GUMBOS against antibiotic-susceptible and antibiotic-resistant clinical isolates of N. gonorrhoeae. Our long-term objective is to have a bank of GUMBOS that can be used as alternative therapy for gonorrhea, particularly for strains of N. gonorrhoeae resistant to conventional antibiotic therapy.

Additive manufacturing and stem cell recruitment for enhancing osseointegration

Shaomian Yao, Shengmin Guo (LSU A&M) and Thomas Lallier (LSUHSC-NO)

Dental implants are a preferred method for the replacement of missing teeth. Osseointegration, the connection of the implant to the surrounding bone, is critical for successful implantation. The shortfalls of current dental implants include the slow or incomplete osseointegration and the gradual loss of osseointegration over time. This research aims to address these shortfalls through the recruitment of endogenous mesenchymal stem cells (MSCs) to implants for rapid osteogenesis and the modification of the internal 3D structures of implants. The long-term goal is to use advanced manufacturing 3D printing techniques to generate patient-specific implants capable of rapid formation of strong osseointegration. This project will not only have a significant impact on the application of guided bone regeneration in dental implantology, but also on the improvement of the design and fabrication of other bone implants.