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RESEARCH PROGRAM INVESTIGATOR FIRST NAME INVESTIGATOR LAST NAME PROJECT TITLE AND DESCRIPTION METHOD(S) OF APPLICATION Cell Biology Julie Brill The student will conduct a genetic screen to identify genes involved in phosphatidylinositol lipid signaling using Drosophila melanogaster as a model system. In addition to fruit fly genetics, the student will learn basic cell and developmental biology. Email: [email protected] Cell Biology John Brummell Student will examine bacterial infection of human cells. Experiments will involve tissue culture, DNA transfections, bacterial infections, and immunofluorescence microscopy. Email: [email protected] Cell Biology Sergio Grinstein Cells of the innate immune system engulf and kill pathogenic bacteria. This process is often disrupted by certain pathogens that manage to survive intracellularly. Email: [email protected]

SickKids Research Programs

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RESEARCH PROGRAMINVESTIGATOR FIRST NAMEINVESTIGATOR LAST NAMEPROJECT TITLE AND DESCRIPTIONMETHOD(S) OF APPLICATION

Cell BiologyJulieBrillThe student will conduct a genetic screen to identify genes involved in phosphatidylinositol lipid signaling using Drosophila melanogaster as a model system. In addition to fruit fly genetics, the student will learn basic cell and developmental biology.Email: [email protected]

Cell BiologyJohnBrummellStudent will examine bacterial infection of human cells. Experiments will involve tissue culture,DNA transfections, bacterial infections, and immunofluorescence microscopy.Email: [email protected]

Cell BiologySergioGrinsteinCells of the innate immune system engulf and kill pathogenic bacteria. This process is often disrupted by certain pathogens that manage to survive intracellularly.

The project will utilize molecular biology and advanced microscopy techniques to elucidate the basic mechanisms of bacterial killing by macrophages and the virulence factors employed by pathogens to co-opt the cellular machinery to their advantage.Email: [email protected]

Cell BiologyWalterKahrThe student will conduct experiments designed to identify key proteins involved in the formation of platelet alpha-granules. To date we have identified two proteins (VPS33B and its binding partner) required for granule biogenesis. The student will utilize immunofluoresence microscopy to localize VPS33B within megakaryocytic cell lines and primary human megaryocytes. To this end, the student will isolate hematopoetic stem cells (CD34+ cells) from human whole blood and promote megarkaryopoesis utilizing recombinant thrombopoetin. Subcellular localization studies will be performed using antibodies specific for various intracellular compartments in concert with GFP-tagged VPS33B.Email: [email protected]

Cell BiologyPeterKimDefects in Peroxisome biogenesis are the cause of numerous genetic disorders involving peroxisomes. In order to develop therapeutic treatments for these disorders, the mechanism of peroxisome biogenesis needs to be understood. Using live-cell imaging techniques in combination with molecular biological techniques the student will aid in the development of assays to detect peroxisome biogenesis in mammalian cultured cells. This work will compliment the ongoing work being carried out in understanding peroxisome biogenesis.Email: [email protected]

Cell BiologyMathieuLemaireOur lab has two main "arms". First, we have expertise in doing gene discovery using whole exome sequencing with a focus on patients with rare pediatric kidney disease. Second, we then perform functional analyses in cell and animal models to figure out how/why the novel genes identified through our genomic studies cause disease. Right now, our efforts are channeled into delineating the pathophysiological processes that lead to the formation of blood clots in small vessels of the kidneys of infants that have mutations in a gene named DGKE. This condition, atypical hemolytic-uremic syndrome, is serious for patients because most develop renal failure. A better understanding of the disease should help identify potential treatments - currently there are none.Email: [email protected]

Cell BiologyChristophLichtAtypical hemolytic uremic syndrome (aHUS) is a devastating form of thrombotic microangiopathy (TMA) that can be both life and organ threatening. Predisposing mutations in several complement-associated genes, primarily coding for humoural and surface-bound regulators of the complement alternative activation pathway have been identified. The association of complement-associated mutations with aHUS has contributed to major advances in diagnosis and treatment. Mutations have been identified in about half of aHUS patients tested so far, and the remaining sources for gene variants relevant to aHUS onset and progression are likely other thrombosis-associated systems (e.g. coagulation and inflammation) and the vascular endothelium.The aim of this project is to identify aHUS-specific endothelial cell characteristics using blood outgrowth endothelial cell (BOEC) cultures. aHUS pathology involves complement, blood coagulation, infective/inflammatory triggers and the vascular endothelium. We hypothesize that laboratory models can be used to simulate aspects of aHUS pathology by bringing together the humoral and cellular components of the complement, coagulation, inflammatory and endothelial systems, and that these model systems can be used to compare the susceptibility of vascular endothelial cells cultured from aHUS patients and unaffected relatives carrying the same complement mutations.Email: [email protected]

Cell BiologyLisaRobinsonThe student will investigate how proteins which regulate development of the central nervous system also regulate trafficking of cells of the immune system, a key feature of many inflammatory diseases including atherosclerosis, arthritis, asthma, and rejection of transplanted organs. The student will utilize cell culture, gene transfer, and microscopy to study how these proteins, neuronal guidance cues, regulate migration of human white blood cells in inflammation. The student will be involved in experimental design, data collection, record keeping, and data analysis.Email: [email protected]

Cell BiologyWilliamTrimbleThe student will learn a variety of research laboratory techniques including cell culture and protein purification and would be required to use these purified proteins in experiments aimed at understanding how proteins bind to each other to regulate cell division. The student will be expected to also attend laboratory meetings where lab progress is presented, to keep neat and orderly notes on his experiments, and to attend weekly seminars on various areas of cutting edge Cell Biology research.Email: [email protected]

Cell BiologyRaeYeungOur lab has identified among Kawasaki disease patients, a genetic polymorphisms in regulators of intracellular calcium flux which result in increased levels of inflammatory cytokines IL1_ and IL18, and more importantly, increased resistance to the treatment in children with these specific genetic polymorphisms.Our summer student project will focus on functional testing of EBV-transformed cell lines that harbor polymorphisms at candidate calcium regulator genes. The summer student will be involved in the examination of the effect of specific polymorphisms on IL1_ and IL18 production, and its association with IVIG unresponsiveness. Flow cytometry will be used to study calcium flux. The expression of IL1_ and IL18 will be examined at both the genetic and protein levels by qRT-PCR and ELISA, respectively.Email: [email protected]

Child Health Evaluative SciencesZulfiqarBhuttaStudents will join a team of researchers at the SickKids Centre for Global Child Health that is currently working on a series of systematic review projects within our knowledge synthesis platform. Over the course of their placements, students will have opportunities to: 1) develop and execute comprehensive literature search strategies; 2) screen search results and assess potentially relevant articles for review eligibility; 3) abstract study, population and intervention effectiveness data from eligible studies; 4) develop and manage databases; 5) assess study quality using standardized tools; and 6) conduct meta-analyses. Additionally, students will be expected and encouraged to participate in the preparation of manuscripts for publication, and to present study findings at internal meetings and other forums.Email: [email protected]

In Person: Room 11.9805, 11th Floor, PGCRL

Child Health Evaluative SciencesCatherineBirkenWe are developing a multi-disciplinary research network of collaborating child health researchers and practitioners including the Paediatric Outcomes Research Team at SickKids and primary care providers from Toronto communities. Drs. Catherine Birken, Patricia Parkin, and Jonathon Maguire are the lead investigators of TARGet Kids! (The Applied Research Group for Kids). TARGet Kids! represents the largest cohort of healthy preschool-aged children (from birth to 5 years) recruited from primary care in Canada. TARGet Kids! is collecting longitudinal medical evidence on common health problems affecting urban Canadian children. Our cohort also serves as a platform to conduct RCTs to better inform practices in primary care. There are critical gaps in the data available on infants and preschool children in Canada. Despite clear significance of the first 1,000 days of life being associated with long-term well being, very little is known about the health of young children. TARGet Kids! addresses these issues and is the first network of its kind in Canada. We propose the project for a summer student which includes data collection (e.g., nutritional status and markers of obesity, such as waist circumference, BMI) at a primary care centre in the community, and/or assistance with data entry. This student will also be assigned a small project to describe preliminary results in our study population.Email: [email protected]: 416-813-5979 Address : 686 Bay St., Rm 10.9709, Toronto, ON, M5G 0A4

Child Health Evaluative SciencesMichaelCarcaoDDAVP vs exercise in patients with mild hemophilia A which is better and do they work synergistically in improving hemostasis?

The above study will be conducted in the summer of 2015. Our group at SickKids has in the last several years been conducting exercise studies in patients with hemophilia. Our group has shown that exercising X15 minutes improves clotting ability (increases levels of FVIII, VWF and platelets) in persons with hemophilia.We now want to assess and compare how exercise compares to DDAVP in improving clotting ability. DDAVP (desmopressin) also increases FVIII and VWF levels in persons with mild hemophilia A.We will do a randomized cross over study comparing the effects of DDAVP vs exercise is 40 males (ages: 12-40) with mild hemophilia A. 20 will receive DDAVP first while 20 will undergo exercise first; patients undergo blood work following the first intervention and then will receive the alternate intervention and then again have their blood checked. Testing will include thromboelastography (TEG) and thrombin generation testing (TGT). The student will have many roles:Assisting with organizing the time tables for patient visits; with day to day activities involved in the study: taking samples to appropriate labs; recording of vitals, times when samples taken, etc and can also get involved in the TEG, TGT and platelet function assay studies (PFA) studies.Email: [email protected]

Child Health Evaluative SciencesBrianFeldmanWhen patients and their parent(s) come to the SickKids rheumatology clinic they receive a standard package of questionnaires which they complete by hand. The division will be implementing new electronic versions of these forms (e-form). The primary objective of the project will examine the reliability and validity of the e-form. The secondary objective of the project will examine the patients' and their parent(s)' comfort level with the use of an e-form. The student would be actively involved in recruiting participants for the study, overseeing the administration of the e-form, and data analysis.Email: [email protected]

Child Health Evaluative SciencesGailMcVeyDr. McVeys eating disorder research and knowledge translation activities involve integrating universal, selective, andindicated (targeted) prevention services and coordinating programming and training in prevention with other clinical services, including assessment and treatment of eating disorders. A pilot research study is underway designed to 1) to evaluate the feasibility of implementing and conducting research on a mental health promotion program being delivered by local public health nurses female students in secondary school; and 2) to assess its preliminary efficacy in improving perceived stress, coping skills, peer and school connectedness, assertiveness, and self-worth. The research is also evaluating what is the ease of participating in each component of the project for each of the stakeholders, including the prevention program group facilitators, the students, and the professionals involved in the advisory/planning group for this initiative. Professional development research is underway also in the area of weight bias awareness, mental health promotion and ways to integrate the prevention of eating disorders with other weight related issues.Mail: 555 University Ave, Toronto, Ont M5G 1X8

Child Health Evaluative SciencesShaunMorrisDevelopment of research program to study health of children traveling to tropical/low income destinations at the SickKids Family Travel Medical Clinic. Topics include compliance with travel recommendations and prophylaxis, follow up surveys for illness and health service usage while overseas, and assessment of risk behaviours/activities. Project will involve development of research questions, surveys, ethics board application(s), and in person and telephone interviews.Email: [email protected]

Child Health Evaluative SciencesMartinOffringaThe Enrich team will be compiling a database of pediatric clinical trial protocols and reports. We seek to employ up to four summer students to select and screen protocols for inclusion into this database. This database will be used as a primary source of empirical data for a variety of different research objectives. We are looking for students who are interested in pediatric clinical trials that show great attention to detail. Experience with database management / computer programming is an asset. Students will gain insight into the methods of modern pediatric clinical trials.Email: [email protected]

Child Health Evaluative SciencesBonnieStevensWe are developing a knowledge translation tool to facilitate the improvement of pain assessment and management practices and reduce pain for hospitalized infants and children. The tool will include a repository of ready-to-use educational materials on the use of evidence-based practices for healthcare professionals, patients and parents.You will be involved in developing educational materials for improving pain assessment and management practices in hospitalized infants and children, including:1. Preparing story boards for short how-to videos of select pain practices (e.g., scripting, planning materials and setting).2. Creating short animated instructional clips for select pain practices.3. illustrating instructions for select pain practices.Email: [email protected]

Developmental and Stem Cell BiologyGabrielleBoulianneThe Boulianne lab utilizes Drosophila as a model to study brain development and function and to develop models of human aging, neurodegeneration and obesity.Email: [email protected]

Developmental and Stem Cell BiologyNormanRosenblumThe mammalian kidney is formed via a sequence of cell commitment, differentiation and complex morphologic events, mediated in large part by signaling pathways. Our lab is focused on how Hedgehog signaling controls specific types of kidney cells that communicate with other types of resident kidney cells and, in so doing, control the number of nephrons formed and the formation of the renal collecting system. In this project, the student will investigate how renal stromal cells control cells that are destined to become nephrons at the molecular level using ex vivo kidney cultures, techniques to modulate activity of factors controlled by stromal cells and assays of nephron formation.Email: [email protected]

Genetics and Genome BiologyRonaldCohnThe summer research student will be involved in studying molecular mechanisms of muscle regeneration in transgenic animal models that mimic congenital human muscle diseases such as DMD and Laminin1 deficiency. She or he will also assist in analysis of regeneration pathways in acquired models of muscle disease, mainly denervation and immobilization. This process will involve tissue acquisition, cryopreservation, sectioning, and visualization, protein isolation and immunoblotting, as well as nucleic acid analysis such as RT PCR. Additional project will be assisting postdoctoral fellows in repair of genetic material in congenital muscular dystrophies. This will involve molecular cloning, transfections, electroporation, and immune fluorescence.. Other duties will include media preparation, tissue culture, data logging as well as general laboratory upkeep and maintenance.Email: [email protected]

Genetics and Genome BiologyYigalDrorOur lab focuses on the discovery of genetic causes and understanding the pathogenesis of bone marrow failure. There are 2 projects that students may be assigned to 1) In the first project a student will use exome sequencing data to rank candidate causative genes and validate the alterations, or perform functional assays to prove causal relationship between mutations and disease 2) In the second project, a student will study the aberrations in hematopoietic differentiation programs in induced pluripotent stem cell disease models of hematopoietic failure.Email: [email protected]

Genetics and Genome BiologyAnnaGoldenbergThis project is meant for students with experience and interest in computational work as applied to computational biology or computational medicine. The goal of the project is to build a model that would be able to predict gene expression and DNA methylation profiles in a tissue of interest given profiles in another tissue (for a given set of patients) and public repositories such as GTEX. This resource will be extremely valuable for tissues that are not easy to sample and for patients where only expression in blood is available.Email: [email protected]@sickkids.ca

Genetics and Genome BiologyEliseHeonAnalysis and Molecular Validation of Whole Exome Sequence (WES) SNV.This project would involve the bioinformatic assessment of WES data and the subsequent validation of candidate SNV by PCR, Sanger Sequence, Restriction enzyme digest, family segregation. Candidates should have academics in genetics, some experience with public databases(eg. NCBI,OMIM,UCSC Genome Browser), experience with primer design and PCR.Email: [email protected]

Genetics and Genome BiologyStephenSchererAutism is a genetic disorder with over 100 susceptibility genes now identified. Working as a part of a team scientists, the successful candidate will perform laboratory and computer-based experiments studying the role of these genes in clinical and functional research studies.Email: [email protected]

Genetics and Genome BiologyUriTaboriThe most common childhood brain tumor is termed low grade glioma (LGG). LGG behave erratically, where some cancers progress regardless of therapy while others even stop growing spontaneously. We currently use the same treatment to all LGG due to lack of ability to differentiate between subgroups.As a result many of these children survive to adulthood but have significant long term side effects of overtreatment while others die due to tumors which were not diagnosed as potentially lethal. Overall LGG account for 42% of brain cancers seen in children and more than half of long term survivors. The impact of these issues on cancer survivors is therefore enormous.

In recent years new discoveries were made making it possible to find genetic mutations in all LGG leading to LGG formation. Unfortunately, the clinical effects of these findings and how to treat these children differently is still unknown.

Several years ago, we formed the LGG task force. This include several centres in Ontario and the Pediatric Oncology Group of Ontario (POGO). Together we built the largest clinical biological database in the world of children with LGG. We already used this data to show several important clinical points such as the toxic long term effect of radiotherapy, how some patients can be treated with less toxic chemotherapy with excellent outcome and defined rare groups of tumors in this large group of children.In a pilot study, we showed that we can use molecular tests to define good risk tumors which do not require aggressive therapy and a subgroup of LGG which carry mutations exposing these children to risk of tumor transformation and death even 15-20 years after initial diagnosis.

In this study we plan to screen 500 LGG which could not be resected and therefore may recur to all known genetic mutations described. We will use a clinically proven technique which could be used in most laboratories worldwide. We will then correlate these data with 30 years of follow up available to us through POGO. We plan to use this unique information to see which of these tumors will stop progressing and therefore may not require therapy and which will progress and cause patients death. As a part of this study, Dr Bouffet is leading clinical trials which involve specific drugs targeting most of these mutations and will enable us to treat these patients with rational therapy in real time.

This study, the first of its kind, will enable us to perform patient specific management and prevent tumor progression in an era of individualized medicine.Email: [email protected]

Genetics and Genome BiologyRosannaWeksbergIntellectual disability (ID) encompasses a diverse group of genetically heterogeneous cognitive disorders affecting 2% of the population. The development of next generation sequencing (NGS) has dramatically increased the speed at which new gene mutations causing ID can be identified. Our research focuses on identifying mutations in genes that encode modifiers of chromatin structure (epigenes). We have selected for exome sequencing children with ID in addition to growth abnormalities. We will prioritize for downstream analysis sporadic de novo epigene variants in our S-ID cohort using the Disease Annotated Chromatin Epigenetics Resource (DAnCER). Our understanding of the role of genetic dysregulation in ID will pave the way for better molecular tools for earlier diagnosis, more definitive prognosis and improved treatment of patients with ID.The summer student will work closely with a senior PhD student in the lab to identify and validate de novo genomic variants in epigenes that cause ID.Email: [email protected]

Molecular and Structure FunctionJulieForman-KayCFTR is the protein mutated in cystic fibrosis (CF). We are interested in probing the interaction between the two nucleotide binding domains of CFTR that drive its chloride channel function and are important for folding, both impaired by various CF-causing mutations. To date, there is no in vitro assay for this interaction, which would be helpful from a mechanistic perspective as well as for screening compounds for potential therapeutic purposes. Both fluorescence and NMR assays are currently under development in the lab and by summer the student should be in a position to test various disease-causing mutations and compounds.Email:[email protected]

Molecular and Structure FunctionJulienJean-PhilippeSurface glycoproteins on immune cells often play critical roles that dictate responses to invading pathogens. A better understanding of their atomic structure and the three-dimensional molecular complexes they form allows us to gain insight into their specific functions. Dr. Juliens laboratory focuses on the characterization of these B cell receptors by using a combination of biochemical, biophysical, immunological and structural techniques. The study of their interactions with cognate molecules, therapeutics and pathogens is also an active area of research in the laboratory. This molecular understanding provides roadmaps for us to design improved vaccines, and treatments in cancer and autoimmune diseases.Email: [email protected]

Molecular and Structure FunctionJohnParkinsonInnovations in high-throughput sequencing have profoundly transformed our understanding of the relationships between microbial communities (microbiomes) and their environments. In the context of human health, it is becoming increasingly evident that the gut microbiome plays a significant role in the development of inflammatory diseases such as type 1 diabetes (T1D), celiac disease and inflammatory bowel disease (IBD) (1,2). Disturbingly, inflammatory disease incidence has dramatically increased with, for example, the frequency of T1D in Canada rising by 50% in the last decade alone (3). In a series of clinical trials, biologic agents such as probiotics, which have the potential to compensate for dysbiotic gut communities, have emerged as potential therapeutic candidates (4). However, further development of probiotic applications are limited by a lack of detailed, systematic studies that focus on understanding the mechanisms by which probiotic bacteria confer protection. Consequently it is not clear which strains might offer the most effective therapeutic agents for which specific condition. Here the applicant will gain skills in comparative genomics, metabolic modeling and systems biology and perform a systematic comparison of the metabolic capabilities of probiotic bacteria to yield insights into their potential impact on host metabolism.Email: [email protected]

Molecular and Structure FunctionRgisPomsThe Poms lab specialises in the development of computer simulation techniques and their application to the study of biomolecular systems (computational biophysics). Basic knowledge of protein structure and/or statistical mechanics, together with some programming experience, is a plus. Research projects available include a study of elastin, the extracellular matrix protein responsible for the extensibility and elastic recoil of tissues such as skin, lungs, and major arteries; and the study of membrane protein CFTR, an ion channel linked to cystic fibrosis.Email: [email protected]

Molecular and Structure FunctionOliviaRisslandThe success of every organism rests upon proper control of gene expression, and each step in the life cycle of an mRNA provides opportunities for regulation. Rather than existing as naked transcripts, mRNAs are dressed with a variety of protein factors, and these mRNA-protein complexes (mRNPs) represent an important regulatory node for controlling gene expression. Indeed, core mRNP factors are regulated during development and are often dysregulated during cancer progression or viral infection. However, understanding the relationship between biological processes and mRNP regulation has proven to be challenging, both because different genes are subject to different post-transcriptional pathways and because, for any specific gene, mRNPs are diverse, transient and dynamic.The goal of this project is to help answer a fundamental, unanswered questionnamely, how are events at the 3' end of a transcript, where regulatory proteins commonly bind, transmitted to the its 5' end, where translation initiates and decapping occurs? This project requires a multi-faceted strategy to tease apart the large diversity of mRNPs, and, accordingly, we will use a powerful combination of classical molecular biology techniques and high-throughput approaches.Email: [email protected]

Molecular and Structure FunctionJohnRubinsteinOur biophysics/biochemistry laboratory uses electron cryomicroscopy to investigate the structures of large macromolecular assemblies. Several assemblies that are of interest in the laboratory are the V-ATPase that controls the pH in various intracellular compartments and ATP synthases that create the cell's supple of ATP. Summer projects are geared to the strengths and interests of the applicant.Email: [email protected]

Molecular and Structure FunctionSimonSharpeSerum amyloid A (SAA) is a 104 amino acid apolipoprotein normally associated with high density lipoproteins (HDL). In response to acute inflammation, SAA serum concentrations increase up to 1000x for 24-48 hours. The precise function of SAA in the inflammatory response is currently unclear, although it is highly conserved in vertebrates, and likely plays roles related to both innate immune response and in cholesterol metabolism near sites of vascular injury. In cases of chronic inflammation due to diseases such as rheumatoid arthritis, rheumatic fever (any that cause inflammatory responses), it has been shown that SAA deposits as amyloid plaques in the kidneys, liver and heart. The resulting secondary systemic amyloidosis can result in organ failure and death, and significantly complicates the treatment of the underlying disease. No structural details of HDL-bound SAA, or of SAA misfolding and assembly into pathological amyloid fibrils, have been reported. We are using an NMR-based approach to determine the structures of SAA bound to HDL particles and in amyloid fibrils. This will provide new details regarding the normal biological functions of SAA in the inflammatory response, and will suggest ways of controlling/inhibiting the aberrant misfolding and aggregation that lead to systemic amyloidosis.Email: [email protected]

Neurosciences and Mental HealthJulieLefebvreIn the developing brain, an astounding number and assortment of neurons are precisely assembled into neural circuits. Formation of accurate connections is imperative for proper wiring and functioning of the nervous system. And it is important to understand how abnormalities in these events underlie brain and neurodevelopmental disorders. The student will join a new research team studying the molecular and cellular rules that shape neurons and their connections in the developing nervous system. Neurons display a remarkable diversity of shapes and their processes dendrites and axons extend to specific targets. To uncover these rules, my lab studies molecules present at the cell surface that serve as recognition codes and govern the interactions of developing neural processes. In this project, the student will investigate the role of a large family of recognition molecules called protocadherins in mouse retina and brain. The student will receive considerable attention and training in molecular biology, neuroanatomy and microscopy techniques.Email: [email protected]

Neurosciences and Mental HealthDonaldMabbottOur lab is particularly interested in understanding the links between white matter injury, neuronal function and neurocognitive impairment following cranial radiation. We do this by integrating several neuroimaging techniques such as Magnetoencephalography (MEG), MRI approaches such as Diffusion Tensor Imaging (DTI) that measure functional (MEG) and structural (DTI and MTI) changes in children treated for brain tumours. We are looking for summer students to help in database management, image preprocessing, and analysis of our MRI and MEG studies. A background in practical experience with MRI, MEG and/or EEG, related softwares (Analyze, FSL, Matlab), statistical packages (SPSS, SAS), and the Linux operating system is strongly preferred.Email: [email protected]

Neurosciences and Mental HealthStevenMillerIdentification of risk factors predictive of neurodevelopmental outcome in neonates who are critically ill. We use advanced brain imaging and detailed long-term follow-up to better understanding brain injury and development in the newborns who are born early or with conditions that put them at risk of neurological and developmental deficits.Email: [email protected]

Neurosciences and Mental HealthStevePrescottNeurons encode information using action potentials, or spikes. How neurons generate spikes influences the way in which neural networks transmit and process information. We aim to decipher exactly how neuronal properties and microcircuit structure impact whether information is encoded through spike rate or through precise spike-timing correlations (synchrony). Understanding this relationship will help explain how network function becomes pathologically disrupted in certain disease states. The student will undertake computer simulations and mathematical analysis of data. Experience with MatLab is a major asset. Student must have completed at least 2 years of undergraduate training by the start of summer to be considered for a position.Email: [email protected]

Physiology and Experimental MedicineChristopherCaldaroneUsing flowcytometry to determine the relative contribution of endothelial-to-mesenchymal transition in the pathogenesis of pulmonary vein stenosis.Email: [email protected]

Physiology and Experimental MedicineAndreaDoriaThe overall survival of children with high-grade or metastatic soft tissue sarcomas (STS) remains dismal. Surgical resection with pre-operative neoadjuvant chemo- and radiotherapy remains the main choice of treatment for these patients. Increased tumor hypoxia (representing decreased local vascularity) may lead to resistance to therapy which is associated with decreased survival and increased metastatic potential in STS. The little progress in the survival of most patients with high-grade STS in recent decades highlights the urgent need for improved hypoxia-targeted diagnostic methods to determine response to therapy prior to surgery of tumors, and for development of targeted therapeutic agents.

We propose to test the feasibility of using novel/existing imaging technologies focused on hypoxia measurements to determine response to therapy in pediatric STS. Specifically, we will compare the sensitivity of Blood Oxygen Level Dependent [BOLD] and DiffusionWeighted [DW] MRI with that of conventional MRI to detect measurement changes between the start and completion of pre-operative neoadjuvant therapy (response to therapy) in children and adolescents (7-18 years) with resectable biopsy-proven tumors. These patients will undergo MRI prior to and after chemo- and/or radiotherapy. We will also evaluate associations between post-neoadjuvant therapy measurements obtained with BOLD, DW and 18F-FAZA PET-CT and immediately obtained surgical / histochemistry outcomes in the residual tumor in the study population. Increased (>95% tumor area) necrosis and decreased (