Research Center News: Trainees
(graduate students, postdoctoral associates and clinical associates)

2012 

Jennifer Krcmery is a young scientist with plenty of determination. As a graduate student completing her research training in the laboratory of Hans-Georg Simon, PhD, Jenny is the picture of optimism, hard work and unflagging energy.

When she first came to the lab, Simon’s research was focused on biological processes that can affect limb development – specifically, mechanisms that result in arm or leg deformities. He and Jenny soon realized that the genes that were causing limb deformities were also affecting heart development. This is the area of research in which Jenny decided to specialize.

“We found that a protein called PDLIM7 is important for mammalian heart valve formation. The heart valves are what allow unidirectional blood flow in the pumping heart so blood doesn’t flow back in the wrong direction. The significant thing about this research is that about 30 percent of cardiac defects involve valves. Many people need to have valve replacements, and some don’t know they have valve problems until it’s too late. So we’re asking a lot of questions. Are there ways that we can use PDLIM7 as a screening tool for patients? If so, are there things we could do to help these patients, such as modifying their daily activities – exercising more or less to support heart function?”

A student in the Integrated Graduate Program (IGP) in Life Sciences at Northwestern University, Jenny was awarded a NIH predoctoral fellowship for her project proposal.

Jenny’s personal story influenced her decision to pursue biomedical research. “I was born with one leg shorter than the other. At that time, there were many cases of what’s called proximal femoral focal deficiency, and the normal procedure was to amputate. My parents went to see several doctors and finally found one, Lorin Brown, who was thinking outside the box. He told my parents about new techniques to do limb lengthening instead of amputation. So we went that route. Every time I would grow, I would have a surgery to catch things up.” As a result of these surgeries, Jenny now leads a normal life.

She continues: “I got into research in some ways because my parents and Dr. Brown didn’t think in the conventional way. A lot of research is like this, trying to develop new techniques or methodologies. If they hadn’t taken a risk, I think my leg probably would have been amputated. I’m an example of why we need people who take risks and make advancements." 

2011 

Abnormal deposition and aggregation of human alpha-synuclein (hSNCA) are observed in a group of neurodegenerative disorders termed synucleinopathies, including Parkinson’s disease (PD). Previous studies have investigated aberrant expression of SNCA coding regions, yet few have described non-coding (NC) region functions. A study by the laboratory of Martha C. Bohn, PhD compared the effects of including a portion of the native 3’ untranslated region (3’UTR) of hSNCA. The results suggest that this inclusion protects against the hSNCA-induced loss of nigrostriatal-projecting dopamine neurons (DA), and that mis-regulation of hSNCA expression and function at NC regions contributes to PD pathogenesis. The study highlights the importance of NC regions and post-translational modifications in the regulation of hSNCA expression and toxicity in DA neurons. The results are relevant to aberrant SNCA expression and function underlying synucleinopathies, and to the discovery of regulatory molecules as potential therapeutic targets for these disorders. Christina Khodr, PhD, postdoctoral associate in the Bohn laboratory, was first author on the publication which appeared online in Developmental Neurobiology in October 2011.

(Image left): Triple labeling of dopamine neurons in rat substantia nigra in a study of effects of alpha synuclein mutants on survival of dopamine neurons (Christina Khodr, PhD). 

  Zhaolin Zhang, PhD 

Cystic fibrosis transmembrane conductance regulator (CFTR) is a large gene that when mutated causes cystic fibrosis. It shows complex cell-type specific and temporal regulation and a wide range of expression levels in different cell types. The low levels of CFTR gene expression and protein in human airway epithelial cells are not easily reconciled with the pivotal role of the lung in cystic fibrosis pathology. Previous data suggest that the regulatory mechanisms controlling CFTR gene expression might be different in airway epithelium compared to intestinal epithelium where CFTR mRNA and protein is much more abundant. The laboratory of Ann Harris, PhD examined chromatin structure and modification across the CFTR locus in primary human tracheal and bronchial epithelial cells and airway cell lines. They identified regions of open chromatin that appear selective for primary airway epithelial cells and showed that several are enriched for a histone modification that is characteristic of enhancers. Three of these sites encompass elements that have cooperative enhancer function in reporter gene assays in airway cells. Finally, they observed long range interactions between the promoter and regions far outside the locus in cell types that express high levels of CFTR. The results were published online in the September 2011 issue of the Journal of Cellular and Molecular Medicine. Zhaolin Zhang, PhD, postdoctoral associate in the Harris laboratory, was first author.

The American Heart Association (AHA) presented a check for $52,000 to the research center for graduate student Sarah Mercer’s project entitled “Naturemimetic extracellular signals for cardiac muscle regeneration” at an event at the research center on November 1, 2011. Mary J.C. Hendrix, PhD welcomed William Roach, national board chairman of the AHA and other guests from the AHA and the community. Following her remarks, Mercer’s mentor, Hans-Georg Simon, PhD thanked the AHA and described how the award will allow young researchers like Mercer to participate in an environment that will ultimately lead to new and better ways to prevent and treat cardiovascular disease. A reception followed.

(From left): William Roach, Sarah Mercer, Hans-Georg Simon, PhD, Mary J.C. Hendrix, PhD 

Zebrafish (Danio rerio) is an excellent model organism for the study of vertebrate development including skeleton formation. Studies of mammalian cartilage formation have been greatly advanced through the use of a cartilage specific regulatory element of the Collagen type II alpha 1 (Col2a1) gene. In an effort to isolate such an element in zebrafish, Rodney Dale, PhD and Jacek Topczewski, PhD analyzed col2a1a, which is expressed in both the stacked chondrocytes (cartilage-producing cells) and the perichondrium (a thin layer of cells that surrounds the developing cartilage). By comparing the genomic sequence around the predicted transcriptional start site of col2a1a among several species of teleosts (fish with bony skeletons), the researchers identified a small highly
conserved sequence (R2) located upstream of the presumptive transcriptional initiation site. The identified regulatory elements enable the tracking of cellular development in various tissues. Using a reporter gene driven by the R2 regulatory element, they analyzed the morphogenesis of the notochord sheath cells as they withdraw from the stack of initially uniform cells and encase the inflating vacuolated notochord cells. Finally, they showed that craniofacial expression of these reporter constructs depends on Sox9a transcription factor activity. At the same time, notochord expression is maintained after Sox9a knockdown, suggesting that other factors can activate expression through the identified regulatory element in this tissue. The study was published in the September 15 issue of Developmental Biology and was featured on the cover (shown left). First author Dale is a postdoctoral associate in the Topczewski laboratory, Developmental Biology Program.

 
Austin Gillen 

The CFTR (cystic fibrosis transmembrane conductance regulator) gene shows a complex temporal and spatial pattern of expression that is controlled by multiple cis-acting elements interacting with the basal promoter. Although significant progress has been made towards understanding these genomic elements, there have been no reports of post-transcriptional regulation of CFTR by miRNAs (microRNAs). Graduate student Austin Gillen in thelaboratory of Ann Harris, PhD, Human Molecular Genetics Program, identified two miRNAs, hsa-miR-145 and hsa-miR-494, which regulate CFTR expression by directly targeting discrete sites in the CFTR 3’ UTR (untranslated region). This research was published in the August 15, 2011 issue of Biochemical Journal. They showed that at least 12 miRNAs are capable of repressing endogenous CFTR mRNA expression in the Caco- 2 (intestinal) cell line. Ten of these also inhibit expression of a reporter construct containing the CFTR 3’ UTR in one or more cell lines, and five repress endogenous CFTR protein expression in Caco-2 cells. Moreover, at least three are expressed in primary human airway epithelial cells, where CFTR expression is maintained at low levels in comparison with intestinal cell lines. The research suggests that these miRNAs may play a more general role in regulating chloride transport in epithelial cells.

Gillen and Harris were also authors of a review article regarding the role of CTCF, which binds insulator elements in vertebrates, in the coordination of gene expression at several gene clusters. The article was published in the October 2011 issue of Biochemistry and Cell Biology. 

From top: Amanda
Becerra, Abby Halpern, Christina Grace Tarazi,
Karolina Kucybala,
Karl-Frederick Vieux 

Thesis Defense 

Diana Himmelstein, a graduate student in the Northwestern University Interdepartmental Neuroscience PhD Program, defended her thesis on June 13, 2011. The title of her talk was “Dynamic regulation of multimerization is required for sonic hedgehog transport and signaling”. Himmelstein is a member of the laboratory of Jhumku Kohtz, PhD, Developmental Biology Program.

Thrasher Award 

Claudia Crowell, MD, a clinical fellow in the Division of Infectious Diseases, received a Thrasher Research Fund Early Career Award for her research in Mali, West Africa, entitled: “Resistance in HIV-1 non-subtype B in children failing first-line antiretroviral therapy”. 

Guifa Xi, MD, PhD,
winner of the
Research Staff
award at Research Scholars Day 2011 

Research Scholars Day 2011 

The seventh annual Research Scholars Day, hosted by the Department of Pediatrics at Northwestern University Feinberg School of Medicine, in association with Children’s Memorial Medical Center, was held on May 11. Award winners from this showcase of research being conducted by fellows, graduate students and research staff were:

First Year Fellows

Stephannie Baehl, MD — Neonatology (Mentor: Karen Mestan, MD): “Intrauterine inflammation, birth weight discordance, and early postnatal growth: a preterm infant twin study”;

Anna Fishbein, MD — Allergy and Immunology (Mentor: Ramsay Fuleihan, MD): “IL-10 is a marker of tolerance to egg protein in peripheral blood mononuclear cells”.

Second Year Fellows

Jennifer Check, MD — Neonatology (Mentor: Karen Mestan, MD): “Small for gestation infants with BPD at increased risk of pulmonary hypertension: a case-control study”;

Jill Samis, MD — Endocrinology (Mentor: Reema Habiby, MD): “The role of microRNA regulation in childhood craniopharyngioma”.

Third Year Fellows

Amanda Brooks, MD — Critical Care (Mentors: Eric Wald, MD and Jerome Lane, MD): “Predictive power of cystatin C (cysC) to detect acute kidney injury in pediatric cardiac surgery patients”;

Bria Coates, MD — Critical Care (Mentor: Conrad Epting, MD): “Determinants of transendothelial migration of Trypanosoma cruzi”.

Research Staff

Guifa Xi, MD, PhD — Research associate, Falk Brain Tumor Center (Mentor: Tadanori Tomita, MD): “Efficacy of vincristine administered via convection-enhanced delivery in a rodent brainstem tumor model documented by bioluminescence imaging”.

Postdoctoral Associates

Christina Khodr, PhD — Neurobiology Program (Mentor: Martha Bohn, PhD): “Inclusion of a 3’UTR containing the microRNA-7 binding site reduces toxicity of human SNCA on striatal-projecting dopamine neurons in rat substantia nigra”;

Hrishikesh Mehta, PhD — Hematology/Oncology/Transplant (Mentor: Seth Corey, MD, MPH): “Why do children with Shwachman-Diamond syndrome or Kostmann syndrome get leukemia? The role of the truncated G-CSF receptor”.

Promise for PD Gene Therapy 

Parkinson’s disease (PD) is a neurodegenerative disorder that currently lacks therapies that halt or reverse disease progression. Christina Khodr, PhD, Martha C. Bohn, PhD and colleagues have been investigating the feasibility of developing an RNA interference-based gene therapy targeting alphasynuclein for PD. An article published in the June 13, 2011 issue of Brain Research presents findings that demonstrate behavioral protection after alphasynuclein gene silencing in a rat model of PD. Although the silencing vector had unanticipated side effects, the observed behavioral protection suggests that alpha-synuclein gene silencing may hold promise as a PD gene therapy upon further silencing vector refinement. This publication also will be featured on the journal cover. Khodr is a postdoctoral associate in the Bohn laboratory, Neurobiology Program of the research center.

(Image left): Chronic expression of human synuclein in dopamine neurons in the brain stem leads to alpha-synuclein accumulation and a time-dependent loss of dopamine neurons. (Christina Khodr, PhD) 

MSCI Scholarships 

Three clinical fellows and one junior faculty member have received scholarships sponsored by the research center for the Master of Science in Clinical Investigation (MSCI) degree program at Northwestern University for the 2012 academic year. This program is intended for medical residents, fellows and junior faculty members who wish to receive formal training in clinical research.

This year’s recipients are:

Stephannie Baehl, MD, Fellow,Neonatology;
Rebecca Carl, MD, Assistant professor, Sports Medicine;
Stephanie Castrillo, MD, Fellow, Neonatology;
Maheen Quadri-Sheriff, MD, Fellow, General Academic Pediatrics.

AMA Award to Jessica Naiditch, MD 

In 2011, the American Medical Association (AMA) Foundation awarded research grants to 37 junior investigators. The Seed Grant Research Program provides medical students, residents and fellows with grants of up to $2,500 for basic science or clinical research projects. Jessica Naiditch, MD, a clinical fellow in the laboratory of Mary Beth Madonna, MD, Cancer Biology and Epigenomics Program, received an award for a study of neuroblastoma (NB), a common pediatric tumor that often presents at a late stage, with only a 20 to 35 percent survival in this group. The goal of Naiditch’s research is to identify the basic biological processes that regulate drug resistance, or the adaptation of malignant tumor cells to stressful environments, such as those produced by anti-cancer drugs, that permit their survival in the presence of agents that would normally kill them. Her group has taken an interest in the role of cancer stem cells (CSCs) in drug resistant neuroblastoma, a new line of research. Naiditch hopes to identify the CSC in neuroblastoma and define its role in drug resistance. 

Adhesive small bowel obstruction (ASBO) develops in about five percent of children and adolescents after major abdominal surgery. The aims of a study published online in the March 2011 issue of Journal of the American College of Surgeons were to describe the current use of operative management in children and adolescents with ASBO and investigate the association between operative delay and the rate of small bowel resection (SBR). All patients 2 to 20 years of age admitted with ASBO in the 2003 and 2006 Kids’ Inpatient Database (KID) were identified. Of these, 85.5 percent underwent operative intervention with lysis of adhesions (LOA) or small bowel resection. Factors associated with the use of operative intervention included younger age, race, and management at a children’s hospital. The time from admission until operation was significantly longer in patients who underwent SBR compared with LOA. Compared with patients who underwent surgery within the first day after admission, the adjusted odds of SBR were similar on the second day after admission but increased when surgery was performed on days 3-14. The majority of children and adolescents admitted with ASBO currently undergo operative management, and 16.4 percent of these patients receive SBR. Operative intervention should be considered in patients who do not exhibit signs of improvement by the second day after admission to avoid potentially increasing the risk for bowel loss. First author Timothy Lautz, MD is a clinical fellow in the Madonna laboratory. 

2010 

 Two Northwestern University undergraduate students, Monica Yang and Gautham Vaidy, received summer research grants from the Weinberg College of Arts and Sciences of Northwestern University to support their summer research in the laboratory of Yong-Chao Ma, PhD, Developmental Biology Program.
 

Christopher Ott, a graduate student in the laboratory of Ann Harris, PhD, director of the Human Molecular Genetics Program of Children's Memorial Research Center, defended his thesis on May 20, 2010. The title of his talk was “Chromatin structure and conformation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene”. He is a graduate of the (IGP) at Northwestern University. In her introduction Harris said that Ott developed and applied state of the art technologies to his work on the CFTR gene, and has moved the field forward. She added that in making many important contributions to the research center training program and in his other leadership roles, Ott has inspired others. In September he will begin a postdoctoral fellowship at the Dana Farber Cancer Institute of Harvard Medical School in the laboratory of James E. Bradner, MD. He will be developing novel chemical biology tools to target transcription factors and chromatin modifying enzymes that are overactive in cancer.

Kathryn Meyer, a graduate student in the laboratory of Jill Morris, PhD, Human Molecular Genetics Program, defended her thesis on March 26, 2010. The title of her talk was “Expression and function of Disrupted-In-Schizophrenia 1 in the developing mouse hippocampus”. She is a graduate of the Northwestern University Interdepartmental Neuroscience (NUIN) Program. Meyer’s accomplishments during her career at the research center include:

• Participated in the Neuroscience in the Early Years: Predoctoral Training Program through NUIN;
• Participated in the Neurobiology of Information Storage Training Program (NISTP) through NUIN;
• Presented the 2009 alumni lecture at the annual meeting of the NISTP;
• Published a seminal research study using in-utero electroporation of the developing mouse hippocampus in Human Molecular Genetics, 2009. A figure from the research was featured on the cover of the journal.

Meyer has begun a postdoctoral fellowship in the laboratory of Samie Jaffrey, MD, PhD at Weill Cornell Medical College. Her research will focus on identifying the roles of RNA regulation in neuronal growth, plasticity and development.

At the spring 2010 meeting of the Center for Genetic Medicine’s Mouse Genetics Group, Northwestern University, two research center graduate students won top awards in the poster competition. Chris Heier, DiDonato laboratory, Human Molecular Genetics Program, received first place. Second place went to Diana Himmelstein, Kohtz laboratory, Developmental Biology Program. Heier is an IGP student; Himmelstein is in the NUIN Program.

Chris Heier (left) and Diana Himmelstein 

2009 

Tyler Schwend, IGP student in the laboratory of Sara Ahlgren, PhD, Developmental Biology Program, defended his thesis on December 18, 2009.  The title of his talk was "Elucidating the spatiotemporal requirement for zebrafish Hh-signaling in craniofacial skeleton development." Schwend has accepted a position as a postdoctoral research fellow at Kansas State University.

The Hedgehog (Hh)-signaling pathway plays a critical role in craniofacial development. Disruption of this pathway in humans can lead to Holoprosencephaly (HPE), which is often characterized by a variety of craniofacial defects. Lipid-modified Hh-ligands require the receptor Dispatched 1 (Disp1) for proper secretion from Hh-synthesizing cells to the extracellular field where they act on target cells. In the December 2009 BMC Developmental Biology, Schwend and Ahlgren studied chameleon mutants lacking a functional Disp1. These mutants display reduced and dysmorphic mandibular and hyoid arch cartilages and lack all ceratobranchial cartilage elements. The study shows that inhibiting the Hh-signaling pathway at early developmental stages selectively reduces anterior facial cartilages, while blocking the pathway at later stages selectively inhibits posterior cartilage development. These findings may help explain the spectrum of human facial phenotypes characteristic of HPE. Schwend is a recent graduate of the IGP and a former student in the Ahlgren laboratory.

In their review article “Fishing for the signals that pattern the face” in the Journal of Biology, December 2009, Thomas F. Schilling and Pierre Le Pabic discuss the findings in the Schwend BMC Developmental Biology paper.

Chondroitin-4-sulfotransferase-1(C4ST-1)/carbohydrate sulfotransferase 11 (CHST11) is an enzyme involved in the biosynthesis of the glycosaminoglycan chondroitin sulfate. The sulfation pattern of chondroitin is tightly regulated during development, injury and disease. The laboratory of Michael Klüppel, PhD previously showed that a mutation in C4st-1 leads to severe skeletal abnormalities during mouse embryogenesis. In addition, they described a highly specific temporal and spatial expression pattern of C4st-1. However, the transcriptional regulatory mechanisms that control C4st-1 gene expression remain unexplored. The laboratory used a bioinformatical approach to identify a functional C4ST-1 promoter, as well as a number of cis-regulatory modules. Moreover, the lab identified TGFß responsive regulatory modules that can function in a cell type-specific fashion. The study was published in the November 2009 Genetics and Molecular Research. Catherine Willis, the first author, is an IGP student. Klüppel is a member of the Human Molecular Genetics Program of the research center.

Intestinal luminal contents contain large amounts of peptidoglycan (PGN), a potent immune adjuvant derived from bacterial cell walls. It influences immunity at the intestinal mucosa and remote sites. How PGN interacts with intestinal epithelial cells and is transported across the intestinal lining remain unknown. In the March 2010 Journal of Cellular Physiology, the laboratory of Xiao-Di Tan, MD characterized PGN transport. Their findings suggest that crypt-based immature intestinal epithelial cells play an important role in transport of luminal PGN, which is transcytosed across intestinal epithelia via a toll-like receptor 2-mediated phagocytosis-multivesicular body-exosome pathway. The absorbed PGN and its derivatives may facilitate maintenance of intestinal immune homeostasis. First authors Heng-Fu Bu, PhD and Xiao Wang, MD, PhD are postdoctoral fellows. Tan is co-director of the Center for Digestive Diseases and Immunobiology of the research center.

PDZ-LIM proteins have wide-ranging and multicompartmental cell functions during development and homeostasis. Facilitating the assembly of protein complexes, they can act as signal modulators, influence actin dynamics, regulate cell architecture and control gene transcription. Recent work in the laboratory of Hans-Georg Simon, PhD has revealed that the protein family member Pdlim7 has important activities at the cellular level, mediating signals between the nucleus and the cytoskeleton, with significant impact on organ development. In the February 2010 BioEssays, the group reviews and integrates current knowledge about the PDZ-LIM protein family and proposes a new role: sequestering nuclear factors in the cytoplasm. The cover photograph for the issue showing a developing coronary vessel and the surrounding myocardium is the work of the Simon laboratory. First author Jennifer Krcmery is an IGP student. Simon is a member of the Developmental Biology Program of the research center.

2008 

Tyler Schwend, graduate student in the laboratory of Sara Ahlgren, PhD, Developmental Biology Program, has been awarded a Ruth L. Kirschstein National Research Service Award for Individual Predoctoral Fellows from the National Institute of Dental and Craniofacial Research. His award is entitled “Sonic hedgehog signaling in zebrafish branchial arch development”. The research will seek to delineate the signaling mechanism whereby the Sonic hedgehog (Shh) pathway promotes zebrafish skeletal development in the branchial arches (jaw and gills) of the fish. Human craniofacial diseases arise from the misregulation of the Shh signaling pathway during early development; a better understanding of its temporal and spatial regulation will be fundamental in helping to explain phenotypic variation in the human disease state.

Cantu and Kerschner selected for CMBD Training Grant 

Jorge Cantu (graduate student in the laboratory of Jacek Topczewski, PhD, Developmental Biology Program) and Jenny Kerschner (graduate student in the laboratory of Ann Harris, PhD, Human Molecular Genetics Program) have been selected as trainees for the Cellular and Molecular Basis of Disease Training Program at Northwestern University. The CMBD, funded through the National Institutes of Health, Institute of General Medical Sciences, is an interdisciplinary and cross-campus program that provides state-of-the-art training in the cellular and molecular sciences for highly qualified predoctoral candidates.