CHANDLER LABORATORY
Our lab is interested in the
regulation of pre-mRNA splicing and how disruption of this regulation can lead
to pediatric diseases such as cancer. Current work in our lab elucidates
alternative splicing as a novel mechanism by which cellular injury can control
the activity of p53 and how changes in the regulation of splicing can lead to
tumorigenesis. The transcription factor p53 is known to induce G1 arrest
of the cell cycle and/or apoptosis. MDM2 is one of the most critical regulators
of p53. Using in vitro biochemical assays and genetically
engineered mouse models we are currently investigating differential RNA
splicing of both the MDM2 and p53 pre-mRNAs and investigating the roles of each
in normal cell function as well as disease.
Another pediatric disease Proximal
Spinal Muscular Atrophy (SMA), the leading genetic cause of infant mortality in
humans, is in part due to a mutation that affects splicing of a duplicated gene
that controls neuronal growth (SMN2). We are interested in generating
viable mouse models for human SMA with the long-term goal of testing candidate
therapies that target the human SMN2 gene. To do this, we
are generating mouse lines that will be utilized to answer many questions
pertaining the therapeutic possibilities of SMN replacement, splicing
correction by drug or antisense treatment, and the correct timing of such
therapies.
Our research represents a novel
perspective in pediatric research that highlights the role of perturbation of
pre-mRNA processing in disease phenotypes. The increased awareness of
regulated RNA processing and recent identification of several disease-causing
mutations that affect splicing give rise to a new generation of potential
therapeutic targets. Point mutations and the resultant splice variants
may both be successfully targeted for therapeutic benefits in the future.
Web Site: http://chandlerlab.nchresearch.org/
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Faculty and Staff
Principal Investigator: Dawn S. Chandler, Ph.D.
e-mail: Dawn.Chandler@nationwidechildrens.org |
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Bebee, Tom
e-mail: Tom.Bebee@nationwidechildrens.org |
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Gladman, Jordan
e-mail: Jordan.Gladman@nationwidechildrens.org |
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Gupta, Reeva
e-mail: Reeva.Gupta@nationwidechildrens.org |
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O'Brien, Dennis
e-mail: Dennis.O'Brien@nationwidechildrens.org |
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Singh, Ravi
e-mail: Ravi.Singh@nationwidechildrens.org |
HALL LABORATORY
Solid tumors are composed of tumor cells and supportive non-tumor components, known as tumor stroma, which can be divided into four main elements: (a.) tumor vasculature, (b.) cells of the immune system, (c.) extracellular matrix, and (d.) fibroblastic stromal cells. Fibroblastic stromal cells can be further subdivided into tumor associated fibroblasts (TAF) that have various levels of genetic and biological abnormalities. Most if not all solid tumors have some degree of tumor stroma, and the presence of reactive stroma often correlates with poor clinical outcomes. Fibroblastic stromal cells have been linked to several activities that promote cancer aggression including enhanced tumor angiogenesis, promotion of epithelial to mesenchymal transition, enhanced tumor cell survival, and progressive cellular genetic instability. In addition, bone marrow fibroblasts (also known as mesenchymal stem cells or marrow stromal cells (MSCs)) have been shown to deregulate anti-tumor immune responses. These observations suggest that fibroblasts can be influential players in progression of metastatic cancer. While a strong argument can be made for the role of stromal cell fibroblasts in tumor progression and metastasis, most of the molecular mechanisms responsible for these observations remain poorly defined.
Rhabdomyosarcoma (RMS) is a childhood muscle neoplasm that affects 1 out of every 33 children who develop cancer, and many children diagnosed with RMS have a poor clinical prognosis, especially if the tumor cells harbor the fusion gene pax3:fkhr or if the tumor has spread beyond the initial site of growth (particularly in cases involving bone metastasis). Likewise, many adult carcinomas (e.g. breast cancer, prostate cancer, and lung cancer) strongly favor the bone as a primary site of metastasis, and typically, the clinical prognosis for these patients is also very poor.
The focus of our lab is to better define the interactions between metastatic tumor cells and fibroblasts and to delineate how these interactions impact tumor growth and survival. We utilize bone marrow fibroblasts known as mesenchymal stem cells or marrow stromal cells (MSC) to model the tumor microenvironment during bone metastasis. Interestingly, MSCs have a propensity to acquire phenotypic and biologic properties of tumor-associated fibroblasts (TAF) when exposed to tumor-derived soluble factors, which in turn may lead to biological enhancement of tumor growth and survival within bone. |
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Faculty and Staff
Principal Investigator: Brett Matthew Hall, Ph.D.
e-mail: Brett.Hall@nationwidechildrens.org |
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Axel, Amy
e-mail: Amy.Axel@nationwidechildrens.org |
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Mundy, Bethany
e-mail: Bethany.Mundy@nationwidechildrens.org |
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Studebaker, Adam
e-mail: Adam.Studebaker@nationwidechildrens.org |
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Sullivan, Nick
e-mail: Nick.Sullivan@nationwidechildrens.org |
LIN LABORATORY
My laboratory studies the cancer biology of Signal Transducer and Activator of Transcription 3 (STAT3) oncogenic pathway and STAT1 tumor suppressor in human cancers. Constitutive activation of STAT3 is frequently detected in most types of human cancers. We are studying the activation of STAT3 by upstream tyrosine kinases, HGF and SDF-1 and how they may function in STAT3-mediated cell survival, proliferation, tumor angiogenesis, and tumor cells/stroma fibroblasts interaction in cancer cells. The laboratory is also developing novel structure-based design of small molecule compounds that selectively target STAT3 oncogenic pathway in cancer cells as a new cancer therapeutic approach. Further, we are examining the interaction between STAT1 and p53 tumor suppressor and how they cooperate to mediate tumor suppression in cancer cells. |
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Faculty and Staff
Principal Investigator: Jiayuh Lin, Ph.D.
e-mail: Jiayuh.Lin@nationwidechildrens.org |
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Ball, Sarah
e-mail: Sarah.Ball@nationwidechildrens.org |
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Chao, Jennifer
e-mail: Jennifer.Chao@nationwidechildrens.org |
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Lin, Li
e-mail: Li.Lin@nationwidechildrens.org |
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Liu, Jian
e-mail: Jian.Liu@nationwidechildrens.org |
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Liu, Aiguo
e-mail: Aiguo.Liu@nationwidechildrens.org |
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Ominoe, Grace
e-mail: Grace.Ominoe@nationwidechildrens.org |
ROSS LABORATORY
Forty years ago, the diagnosis of pediatric acute lymphoblastic leukemia (ALL) was enough to strike terror in a parent's heart. At that time, only 1 out 10 children diagnosed with ALL survived for 5 years. Today, the results are exactly opposite, 8 or 9 of every 10 children diagnosed with ALL will survive for at least 5 years. Researchers around the world have contributed to the understanding of the heterogeneous nature of ALL with regard to underlying genetic lesion, response to therapy, and subsequently risk of disease relapse.
Similarly, completion of the human genome project has led to new understandings and high throughput technologies. One high throughput technology is that of oligonucleotide microarrays which simultaneously query near whole genome gene expression in a sample. During my fellowship, we demonstrated that gene expression profiles can be determined for the diagnostically relevant subtypes of pediatric ALL. Subsequently we demonstrated that gene expression profiles can be used to classify pediatric ALL with high accuracy. Current efforts in my laboratory focus on exploring the relationship of various genes in the gene expression profiles to the underlying genetic lesion. Understanding the mechanisms involved in which genes contribute to a gene expression profile may lead to new insights for targeted drug therapy, mechanisms of resistance, or understanding the leukemogenic process. |
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Faculty and Staff
Principal Investigator: Mary Elizabeth Ross, M.D., Ph.D.
e-mail: MaryElizabeth.Ross@nationwidechildrens.org |
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Braun, Linda
e-mail: Linda.Braun@nationwidechildrens.org |
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Chen, Chun-Liang
e-mail: Chun-Liang.Chen@nationwidechildrens.org |
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Connell, Harkness
e-mail: Harkness.Connell@nationwidechildrens.org |
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Malik, Vinod
e-mail: Vinod.Malik@nationwidechildrens.org |
