2013 St Jude Summer Plus Faculty
My laboratory studies the Hedgehog (HH) signal transduction pathway, which plays an evolutionarily concerved role in patterning fields of cells during metazoan development. Mutation of HH pathway components is causative in pediatric cancers including medulloblastom the most common malignant brain cancer in children, and rhabdomyosarcoma, where HH pathway activation correlates with poor prognosis. We utilize a combination of biochemical and genetic analyses to examine the regulation and signaling mechanisms of two critical HH pathway components: 1) Dispatched (DISP), a 12-pass transmembrane protein that governs release of mature HH ligand from producing cells, and 2) Smoothened (SMO), a G protein coupled receptor (GPCR) that functions as the requisite signaling molecule in HH receiving cells. Our goals are to understand DISP function and SMO signaling in both physiological and pathophysiological processes to better characterize DISP, SMO and their downstream effectors as potential therapeutic targets. To do so, we utilize the fruit fly Drosophila melanogaster as a model organism. The Drosophila model system offers a powerful tool to dissect the HH signaling cascade because HH pathway components are tightly conserved from Drosophila to man, HH phenotypes are well characterized in Drosophila, and the power of Drosophila genetics allows for rapid identification and manipulation of genes involved in HH signaling.
Available summer research project
1). Primary amino acid sequence analysis predicts that DISP contains a regulatory motif known as a sterol sensing domain (SSD). The SSD controls protein function by sensing local concentrations of
cholesterol. Accordingly, the majority of SSD-containing proteins are involved in cholesterol biosynthesis. Given that DISP is not involved in this process, the exact regulatory role of its SSD is not known. However, mature HH ligand is cholesterol modified, suggesting that DISP may monitor HH biosynthesis, and control its release, by sensing HH lipid modification. To better understand the role of the DISP SSD in control of HH ligand release, one project in the laboratory involves mutagenesis and structure/function analysis of the DISP SSD. We will mutate conserved SSD residues in DISP, using standard molecular biology techniques, and assess the ability of DISP SSD mutants to rescue disp knockdown in vitro. We will also generate a DISP SSD expression vector that will express the SSD regulatory domain in the absence of flanking DISP sequence. This will allow us to determine whether the SSD confers dominant effects on endogenous DISP protein. DISP SSD mutants demonstrating altered behavior in vitro will next be assessed in transgenic Drosophila. These studies will provide the opportunity to learn cell biological and biochemical techniques frequently used for in vitro analysis of signal transduction pathways, and will also allow for hands-on experience using the Drosophila model system.
Department of Bone Marrow Transplantation & Cellular Therapy The Dallas lab is focused on improving the outcomes of patient undergoing hematopoietic stem cell transplant (HSCT) using umbilical cord blood (UCB) as an alternative stem cell source. HSCT using stem cells from a human leukocyte antigen (HLA) matched donor is a widely accepted form of therapy for various malignant and non-malignant hematological diseases. However, many patients do not have an HLA-matched donor identified. The use of UCB has significantly increased the donor pool and the number of patients qualifying HSCT. UCB have certain advantages and disadvantages compared to bone marrow or peripheral blood stem cells. Our lab is interested in ex-vivo manipulation and culture of cord blood progenitors that may ultimately have therapeutic potential. Currently, we have three main focuses of the lab. 1. Understanding the unique immunological interactions and barriers involved in cord blood transplantation. In particular the biology of regulatory T cells and antigen presenting dendritic cells. We use unique humanized immunodeficient mouse models, where a human thymic tissue is implanted in the kidney capsule to investigate the immune recovery after transplantation. 2. Ex-vivo expansion of pluripotent hematopoietic stem cells using the Notch signaling pathway. 3. Ex-vivo manipulation of cord blood progenitors using gene therapy to improve engraftment. Participants of the Rhodes College Summer Plus Program will be actively involved in our laboratory team. Depending on the student’s interest, I have identified few well-defined projects that can be accomplished during this research period. The techniques that will be learned include and not limited to: 1. Cell culture 2. Cord blood hematopoietic stem cell isolation 3. Microscopy and imaging of cells culture and tissue 4. Involvement in murine transplantation and surgery
Mari Dallas, MD
The Dallas lab is focused on improving the outcomes of patient undergoing hematopoietic stem cell transplant (HSCT) using umbilical cord blood (UCB) as an alternative stem cell source. HSCT using stem cells from a human leukocyte antigen (HLA) matched donor is a widely accepted form of therapy for various malignant and non-malignant hematological diseases. However, many patients do not have an HLA-matched donor identified. The use of UCB has significantly increased the donor pool and the number of patients qualifying HSCT. UCB have certain advantages and disadvantages compared to bone marrow or peripheral blood stem cells. Our lab is interested in ex-vivo manipulation and culture of cord blood progenitors that may ultimately have therapeutic potential. Currently, we have three main focuses of the lab.
1. Understanding the unique immunological interactions and barriers involved in cord blood transplantation. In particular the biology of regulatory T cells and antigen presenting dendritic cells. We use unique humanized immunodeficient mouse models, where a human thymic tissue is implanted in the kidney capsule to investigate the immune recovery after transplantation.
2. Ex-vivo expansion of pluripotent hematopoietic stem cells using the Notch signaling pathway.
3. Ex-vivo manipulation of cord blood progenitors using gene therapy to improve engraftment.
Participants of the Rhodes College Summer Plus Program will be actively involved in our laboratory team. Depending on the student’s interest, I have identified few well-defined projects that can be accomplished during this research period. The techniques that will be learned include and not limited to:
1. Cell culture
2. Cord blood hematopoietic stem cell isolation
3. Microscopy and imaging of cells culture and tissue
4. Involvement in murine transplantation and surgery
Work in the Pillai lab centers around regulatory T cells in both mice and man. These cells are unique in their ability to both orchestrate and modulate the capacities of almost every other immune cell type, but also to have important roles in anti-tumor immunity. The laboratory studies both of these aspects using murine models of successful transplantation regimens, as well as studying human regulatory T cell subsets in culture. We focus on 2 main groups: 1) innate immune cells (those which do not require antigen exposure to exert immune function), including natural killer T (NKT) cells; 2) adaptive immune regulatory cells (those which require thymic selection and which typically express the transcription factor Foxp3), including CD4+Foxp3+ cells (Treg). Our laboratory has generated unique and potent ways to expand both of these cell subtypes, and we are currently actively characterizing important aspects of their function which have importance both for anti-tumor immunotherapy and for preventing fatal immune complications after allogeneic transplantation such as graft-versus-host disease (GVHD). The laboratory includes 3 seasoned PhD post-doctoral fellows and 1 senior technician, all of whom are very enthusiastic and have demonstrated capacity to mentor students one-on-one. The laboratory is balanced with respect to mouse and human cellular work (2 in mouse, 2 in human).
A student joining this lab would participate mouse models of regulatory T cell function in bone marrow transplantation and the direct translation of mouse work within the lab to human regulatory T cells and their manipulations for pediatric cancer and transplant immunotherapy. Specifically, the student would be given a sub-project of his/her own with the goal of studying an important aspect of receptor signaling in a specific type of regulatory T cells, and how this affects critical immune function of these cells. An alternative project for a student is to work with our technician and an incoming MD fellow in the lab on a mouse model of curative transplantation for hemoglobinopathies, where we have some very promising results; this project is entirely in mice, though we may obtain human samples from an upcoming clinical protocol at St. Jude.
Techniques in which a student can be expected to become very proficient under direct instruction of the PI are: mouse bone marrow transplantation and special surgical procedures, tissue harvesting and histopathologic examination of GVHD, tumor imaging, magnetic cell enrichment, 8-9 color flow cytometry, FACS cell sorting, PCR techniques, immunofluorescent cell imaging and models, sterile tumor line culture, non-radioactive mixed leukocyte reactions (MLR) and tumor killing assays, unique techniques to expand regulatory T cells, multi-parameter FlowJo and Prism® software use, laboratory data and research presentation, and preparation of abstracts and manuscripts (mentored by PI and fellow).
Research in the Rivas Laboratory focuses on the field of natural product synthesis with an emphasis on the development of catalytic asymmetric methods that facilitate the construction of complex molecules of promising pediatric therapeutic value. Lead discovery for the treatment of pediatric malignancies, particularly glucocorticoid resistant acute lymphoblastic leukemia (ALL) and acute myeloid leukemia AML are amongst our priorities. We narrow on strategic bond disconnections promoted enzymatically in nature, which remain inaccessible enantioselectively using modern synthetic methodologies. Current areas of research in the Rivas laboratory include total synthesis of sesquiterpenoids, spiro-indole alkaloids, and the development of catalytic systems for enantioselective electrophilic halogenation. In parallel, our laboratory has an ongoing research program in the area of bioactive-guided terrestrial natural product isolation and chemical structure elucidation in collaboration with Natural Product Museum in Paraguay. Our research integrates the critical areas of synthetic method development, total synthesis and medicinal chemistry.
Learn to design and carry out synthesis of novel chemical entities (spiro-indole alkaloids) for drug discovery through innovative chemical strategies
Learn proper and effective methods to handle highly sensitive, hygroscopic, and air sensitive reagents
Learn to purify reaction mixtures using modern techniques such as HPLC, Isolera purification system as well as standard methods (thin layer chromatography, column chromatography, ion exchange chromatography)
Learn how to use the following programs: Chem. Draw Ultra, SciFinder, ISIS Draw, and Excel for chemists Ability to conduct and/or interpret 1D NMR, 2D NMR, IR/UV, High and Low Res Mass Spectroscopic Data
Learn to critique, present, and write scientific articles
Learn to work in a collaborative multi-disciplinary environment
The student will understand the process of drug discovery from product lead to product optimization, and be able to conduct independent and original research. He/she will have the opportunity to present their work at either local or national meetings and publish their results in peer reviewed journals.
The blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) possess many physical and chemical properties that prohibit xenobiotics from entering the brain parenchyma and ventricular system. While these barriers regulate central nervous system (CNS) homeostasis, they also pose huge therapeutic issues for many CNS diseases. Therefore, the field of brain barrier biology could greatly benefit from the creation of an animal model suitable for molecular dissection of the BBB and BCSFB. Zebrafish provide many advantages for the study of complex biological systems like these brain barriers. They are vertebrates; transparent; small; and develop rapidly outside of the mother. Our preliminary studies and recent work of others demonstrate that zebrafish possess the structural and functional properties of the brain barriers, further indicating the utility of this animal model. To tackle such a complex problem, we plan to exploit the strengths of zebrafish as a model organism as they are amenable for high-throughput genetic and small-molecule screens.
Our recent creation of a BBB transgenic line and a BCSFB enhancer-trap line provide valuable in vivo tools for dissecting the complex molecular components of the BBB and BCSFB. We predict that these studies will identify novel genes that play a role in barrier formation and function as well as small molecules that modulate the BBB and BCSFB. These screens could also lead to the discovery of drugs that permit the controlled access of therapeutic agents into the brain and drugs that help to repair damaged barriers. Embarking on this brain barrier project, students will be exposed to many laboratory techniques, including confocal microscopy, fluorescence immunohistochemistry, transgenic zebrafish, forward genetic screens, and small molecule screens.
The research interests in the laboratory of Dr. Kevin Krull focus on neurocognitive outcomes of childhood cancer and cancer therapy. Various study designs are used to examine the etiology, pathophysiology, treatment, and impact of abnormal brain development in child, adolescent and adult survivors of childhood cancer.
The primary method of data collection employed in the lab involves neuropsychological and behavioral assessments. This data is integrated with structural and functional brain imaging and various other biomarkers to examine the direct impact of cranial radiation and chemotherapy on brain development, as well as cardiovascular, neuroendocrine, and genetic mediators of neurotoxicity. Trials are ongoing to examine the efficacy of various interventions on enhancing neurocognitive functions, including direct cognitive training, improvement in sleep quality, and aerobic exercise. Student obtain experience in neuropsychological assessment and intervention strategies, as well as the integration and interpretation of multi-source data.
Beatriz Sosa-Pineda, PhD
Pancreatic ductal adenocarcinoma is one of the deadliest forms of cancer with a five-year survival of less than 5%. A better understanding of the cellular origins of pancreatic cancer and the role of specific genetic lesions in tumor initiation and/or progression is needed to improve patient outcomes.
Tumor formation is often accompanied by inappropriate activation of signaling pathways or processes that normally operate during organ development. In a preliminary study we found that mice expressing abnormal levels of the transcription factor Prox1, a critical regulator of pancreas development, are more susceptible to form pancreatic tumors. We are currently using various in vivo approaches to fully characterize tumor formation in the previous mutant mice. Likewise, experiments in vitro will be used to identify molecular processes regulated by Prox1 function in pancreatic cancer cell lines.
Rhodes Summer Plus students interested in joining the previous study could assist the characterization of preneoplastic lesions and/or pancreatic tumors from our mouse models using histology and immunohistochemistry techniques. He/she could also participate in the analysis of pancreatic cancer cell lines infected with control or Prox1-expressing retroviruses, or help to establish and characterize primary cell lines from the pancreatic tumors of our mutant mouse models. This student will work under the supervision of Dr. Yiannis Drosos, the postdoc in charge of this project.
Pneumonia is the leading cause of childhood mortality worldwide, killing over one and a half million children under 5 years of age each year. In the United States, pneumonia accounts for over one million hospitalizations and over fifty thousand deaths each year despite availability of antibiotics and administration of vaccines. The human pathogen Streptococcus pneumoniae, is responsible for over 6 million infections each year in the United States. Accumulating evidence suggests metal transporters play an important role at all stages of bacterial infection, and may be suitable targets to control infections. My research focuses on defining the role of these metal transporters in infection, and the development of novel inhibitors to target these transporters as a new strategy to combat infection.
To understand the contribution of these transporters to disease progression, we employ a number of genetic and biochemical techniques. Projects will address a number of important questions including the basis for substrate specificity, transcriptional control of the transporters, and the effects of metal ions on cell signaling pathways. We also will evaluate the specificity and efficacy of novel metal channel inhibitors, as well as the bacterial response to these compounds. This knowledge should provide key insights into understanding bacterial pathogenesis. Major techniques to be utilized throughout this project include PCR, molecular cloning, protein purification, generating bacterial knockouts, transposon mutagenesis screening, Western Blotting, BSL2 culturing techniques, modeling of bacterial pneumonia, DNA and RNA isolation.
Influenza viruses are a major cause of respiratory illness in the United States with symptoms ranging from mild (cough, fever, headache) to severe or even death. In a typical influenza season, the viruses cause approximately 35,000 deaths and 200,000 hospitalizations annually. Occasionally, a particularly virulent strain of influenza virus arises which has the potential to infect many more individuals and cause greater mortality. Very little is known about why certain strains of influenza virus cause a more severe illness than others.
Macrophages are an important cell type of the immune system that are on the front lines of defense against virus infection. The lab of Dr. Stacey Schultz-Cherry has found that only certain strains of influenza virus, those which cause severe disease, are capable of growing in macrophages. This is an important new discovery and may potentially explain why some virus strains cause very severe disease.
The goals for this project are to:
1) Understand the viral protein driving growth in macrophages
2) Determine how these viruses are affecting the macrophage to promote their replication
3) Identify if differences in replication in macrophages impacts severity of disease
This is an exciting, and cutting edge project that will train the student in the following methodologies that are common in the medical and biotechnology fields:
Asceptic cell culture technique
Molecular biological methodologies including reverse genetics and transfection to produce virus-like particles that are commonly used as vaccines
Safe handling of influenza virus under bio-safety level 2 conditions
Protein biochemistry including western blots
Immunological assays including ELISA and Flow cytometry
Mary Relling, PharmD
The goal of our laboratory is to determine the host- and treatment-related factors that contribute to interindividual differences in response of children with acute lymphoblastic leukemia (ALL) to current therapies.
The heterologous enzyme, asparaginase, is an essential component used in the treatment of ALL that has been associated with improve outcome in children. The mechanism of action for asparaginase involves the hydrolysis of the serum amino acid, asparagine, which is required by leukemic cells for cell proliferation. The depletion of asparagine results in the selective cell death of leukemic cells. However, up to 45% of children given asparaginase can develop a hypersensitivity reaction against the drug, and up to 70% of children can develop neutralizing antibodies that can reduce the efficacy of the asparaginase.
The research in our laboratory is exploring the various pathways of hypersensitivity in order to identify the relationship between antigen-specific antibodies, degranulation products, and the severity of hypersensitivity reactions. Emphasis is placed on determining the influence of antibodies and hypersensitivity products on the pharmacokinetics and pharmacodynamics of asparaginase, and on discovering alternative treatment strategies to block the reaction from occurring without influencing the efficacy of asparaginase. Common methods and procedures used in our laboratory include ELISAs (enzyme-linked Immunosorbent assays) to detect antigen-specific antibodies (IgG, IgM, and IgE) and to quantify the levels of mast cell proteases released during hypersensitivity reactions. Spectrophotometric assays are to quantify the concentration of asparaginase in serum, and basic mouse handling techniques are used during experiments designed to model the hypersensitivity reaction in mice. The long-term aim of the project is to improve ALL treatment with asparaginase and to identify patients that might be predisposed to developing hypersensitivity reactions against asparaginase.
The Rhodes student would be part of our laboratory team, working directly under the supervision of a post-doctoral fellow (Dr. Christian Fernandez) in Dr. Relling’s lab. The student would be expected to present at and participate in regular laboratory meetings, communicate freely with other trainees and staff in the laboratory, and attend relevant departmental meetings. By the end of the Summer Plus program, we anticipate that the student will have authorship on at least one peer-reviewed paper and will have an excellent idea of what goes on in a translational research laboratory.
Childhood cancer is widely viewed as a traumatic event, and consequently, study of posttraumatic stress has become a dominant approach in research on psychosocial outcomes in this population. However, this approach to understanding the experiences of children with cancer presupposes ‘cancer as trauma’, and focuses on psychopathology rather than adjustment. This has influenced research design and, we believe, has significantly biased the literature towards an overemphasis on, and overestimate of, negative outcomes. Our study is based on the assumption that the diagnosis of cancer represents a significant life event that is not only a potential trauma, but also a potential catalyst for growth and positive change, calling for examination of positive outcomes such as post-traumatic growth (which we refer to as challenge-related growth) and benefit-finding, constructs that have been studied primarily in adults with cancer but not in children. This study, which is ongoing, involves assessment of both posttraumatic stress (PTS) and positive growth outcomes in a large sample of children with cancer and matched healthy children from the community. Guided by positive psychology theory, we are examining determinants of PTS and growth outcomes, focusing on several resilience-related personality variables, including adaptive style, optimism, and dispositional positive affect. Data is obtained by questionnaires and interview, including diagnostic interviews of both children and parents.
This internship will involve opportunity for direct patient contact. The interested student would be trained in administration of standarized, semi-structured diagnostic interviews, and would participate in all aspects of the day to day running of the study, including identification of potential participants, recruiting/consenting of patients, administration of questionnaires, conducting of interviews, handling of data, and some data analyses. Training and certification in the protection of human research participants will be required. Participation in our weekly laboratory meeting includes a journal club focusing on this area and other related topics in pediatric psychology. The ideal candidate would be majoring psychology or other social science, and interested in clinical research. Given that there will be patient contact, we will be looking for a student with exceptional maturity, good social and communication skills, and a curiosity and enthusiasm for understanding human adaptation.
Claudia Hillenbrand, PhD
Magnetic resonance imaging (MRI) can produce images non-invasively that reveal the morphology, metabolism, and function of internal tissues or organs. MRI offers many ways to manipulate and quantify the image contrast which is the basis of ongoing research of the MR Physics Lab. We focus on the development and application of novel and advanced imaging tests that potentially replace existing, suboptimal diagnostic tests which, for example, apply radioactive substances or are invasive. The team works on MR methods to acquire functional information from different organs in patients with sickle cell disease (SCD) and cancer. We want to provide physicians with the most accurate and effective tools for non-invasive assessment of disease (e.g., organ vitality/damage) and treatment outcome and are currently working on the following main projects:
(a) Non-invasive quantitative assessment of liver iron content in patients with transfusional iron overload. This is a problem in patients with SCD and blood cancers and can lead to iron related toxicity and death. We are working on an accurate MR test that is applicable to patients with extremely high liver iron content and will calibrate our imaging method with biopsies in a patient study planned to start in early 2012.
(b) Use of magnetically labeled targeted nanoparticles with and without a therapeutic payload. These nanoparticles are combined with an antibody and assessed for treatment of solid tumors (neuroblastoma). The nanoparticles are also needed as calibration standards for iron quantification.
(c) Functional assessment of kidney function. This involves the development of non-invasive diffusion and perfusion methods and strategies to compensate or minimize effects on image quality due to the breathing motion. We are further optimizing and applying these methods in a neuroblastoma trial and study the effectiveness of organ sparing radiation therapy with functional MRI and PET methods.
The Rhodes Summer Plus Student would work on a project related to one of these areas, depending on personal preference. For example, in case of the iron overload project, the student will develop model fitting algorithms for the quantitative assessment of iron overload in massively overloaded patients. As we will apply a new imaging strategy, the post processing will have to be adapted. This will include the selection and implementation of algorithms for phase unwrapping of complex MR data sets, and the utilization and characterization of model fitting functions needed to quantitatively describe the decay of the MR signal as a function of the liver iron content. The algorithms will be tested on data of the accompanying patient protocol. The nanoparticles project on the other hand would encompass learning how to operate an MRI scanner, running quantitative MR tests in vials filled with different nanoparticle concentrations and in murine models, and analyzing the data. This project would provide an insight into typical work of a physicist/biomedical engineer specialized in MRI research. The renal function project involves the acquisition and analysis of patient MRIs. A major part will be the co-registration of radiation dosimetry map, PET, and MR scans to study renal function in neuroblastoma survivors after the treatment.
The interested student will work as member of a multi-disciplinary team consisting of MR Physicists, Radiologists, Hematologists, Radiation Oncologists, Biomedical Engineers, and Computer Scientists in the Department of Radiological Sciences at St. Jude Children’s Research Hospital. The student will be given the opportunity to work on an independent research project and summarize the results as a conference abstract and manuscript.
The goal of my research is to understand the effects of catastrophic disease and treatment on brain function in children. My research group utilizes three main MRI techniques to investigate brain function, including functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and perfusion imaging. These techniques allow us to non-invasively evaluate critical elements of functional neural networks in the brain. fMRI is used to measure task- or stimulus-induced brain activity, which is detected indirectly through changes in blood oxygenation linked to changes in neural activity. fMRI reveals the functional cortical networks that are engaged in a task of interest. The activity observed with fMRI is located within gray matter and reflects the coordinated activity of functionally specialized regions of the brain. DTI, a method of measuring the diffusion properties of tissue, is used to characterize and visualize the major white matter tracts in the brain. The tracts are identified by the spatial anisotropy of water diffusion within the highly structured white matter tissue. White matter tracts are essential for communication within neural networks to allow effective and efficient integration of regional brain activity in specialized cortical areas. Perfusion imaging is a method of evaluating cerebral blood volume and flow. In the healthy brain, local changes in cerebral perfusion are tightly coupled with changes in neural activity to support dynamic metabolic demands. These functional neuroimaging modalities require a broad array of technical capabilities, including MRI pulse sequences for data acquisition; image processing and statistical tools for data analysis; and the equivalent of a neuropsychological testing laboratory in the MRI scanner.
We are conducting hypothesis-driven functional neuroimaging studies in three St. Jude patient populations. In patients treated for medulloblastoma, we are using functional neuroimaging to investigate the neural systems activated for reading. My hypothesis is that disruption of commissural connections in the visual system interferes with normal developmental lateralization of brain function during the acquisition of reading skills and causes deficits in reading ability. In patients with Sickle Cell Disease we are investigating the effect of anemia-induced changes in resting cerebral blood flow and volume on stroke risk, response to therapy, and cognitive function. Finally, in patients with retinoblastoma we are investigating the impact of disease and its treatment on visual system development and function. Because retinoblastoma affects the visual system while the central nervous system is still developing, we hypothesize that differences in visual outcome among retinoblastoma patients are caused, at least in part, by differences in disease- or treatment-associated effects on functional development of the primary visual cortex. Participating students will have the opportunity to contribute to all major elements of our functional neuroimaging research, including data acquisition, image processing, and statistical analysis to characterize the effects of demographic, genetic, and medical factors on brain function in the children that we study.
A unique conundrum in computed tomography (CT) radiological imaging is that the more radiation used, the better the image quality outcome. A radiological image is formed by passing bremsstrahlung radiation through the body. The radiation that was not absorbed by the body is then mathematically manipulated into a 2D or 3D image. The conundrum is that increased radiation exposure also increases the risk of adverse health effects. Pediatric patients undergoing radiological imaging are one of the most vulnerable patient populations to radiobiological effects. When optimizing radiological imaging for pediatric patients a unique challenge for users of CT is to lower radiation output (thereby lowering exposure risk) without significantly degrading image quality (i.e. maintaining diagnostic fidelity for radiologist interpretation).
At St Jude, we have developed a novel approach to reduce radiation exposure to our pediatric patient population by implementing a new mathematical reconstruction algorithm as a means to maintain image quality with less radiation. In our first implementation we have demonstrated radiation dose reduction to better than 50% for patients ranging in age from 1 year to adulthood without any change in image quality perception. We currently have several projects planned to (1) fully characterize the nonlinear image quality effects discovered with the new mathematical reconstruction technique, (2) further lower radiation exposure by decreasing overall potential energy of the radiation (kVp) used for image formation, and (3) refine the patient radiation exposure measurement methodology.
Students joining our lab will learn proper techniques for measuring radiation (which includes handling: solid state detectors, ion chamber detectors, a selection of anthropomorphic phantoms, and data post processing), will be taught mathematical principles to optimize image quality (a minimum of calculus will be prerequisite), and will be a part of a project that has been first in the nation to fully characterize these novel dose reduction techniques.
Radiological Sciences and
Chemical Biology & Therapeutics
The principal focus of our efforts in Molecular Imaging Research is the development of novel radiopharmaceuticals and imaging methods for the evaluation and management of children with tumors using positron emission tomography (PET). PET is a medical imaging method that can be used to investigate specific aspects of tumor biochemistry and pathophysiology. Individual projects will combine aspects of Organic Chemistry, Radiochemistry, Biochemistry and Pharmacology and internship opportunities are available in any or all of these areas. A typical project involves the synthesis of precursor molecules for radiolabeling and analytical standards, determination of optimal conditions for radiolabeling with carbon-11, fluorine-18 or other PET radionuclides, biochemical evaluation of the mechanism of action of the new radiopharmaceutical and biological testing in animal models of human disease. Project will involve some handling of radioactivity and experimental animals. Students are encouraged, but not required, to participate in these activities. Students with either chemistry or biochemistry background are encouraged to apply.
Specific research projects include: a) development, in collaboration with researchers at the University of Michigan, of C-11 labeled agents for imaging pheochromocytoma and neuroblastoma, b) radiolabeling and biological testing of an anti-neuroblastoma antibody in production at the St Jude GMP facility, c) biological evaluation of a new radiotracer for monitoring mitochondrial function, and d) design of radiotracers for measuring enzymatic activity involved in activation of a chemotherapeutic currently under development.
Donald Bashford, PhD Mina (Myc induced nuclear antigen), a protein involved in cell proliferation and immune-response regulation, has sequence homology to the JmjC class of enzymes, but its specific substrate and function remain unknown. Recently a crystal structure of Mina has been obtained. The student will search sequence and structural databases to find related proteins, and build comparative 3D structural models, including hypothetical models of Mina interacting with possible substrates. The goal will be to use the new structural data to find clues to function that will guide further inquiries.
The Bashford lab specializes in computational methods including structural modeling and structure-function studies. The Bix lab is focused on understanding Mina from the standpoint of its biological roles and underlying molecular mechanisms.