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Biographical
Sketch
Dr.
Winandy received her PhD in Biology from the Massachusetts Institute of
Technology in 1994. As a
graduate student, she studied the transcriptional regulation of simian
immunodeficiency virus (SIV) in the laboratory of Dr. Nancy Hopkins. Her postdoctoral training was obtained under the guidance of
Dr. Katia Georgopoulos at Massachusetts General Hospital/Harvard Medical
School where she began her studies on transcriptional regulation during T
cell development and leukemogenesis.
She joined the faculty as an assistant professor of
microbiology-immunology in the fall of 2000.
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Research
Description
We
are interested in unraveling how chromatin remodeling complexes are
targeted to specific genetic loci to activate or repress transcription
during T cell development. In
addition, we are studying how abnormalities in localization of these
complexes during T cell development results in leukemogenesis.
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Research
Abstract
During the
process of T cell development, cells undergo changes in patterns of gene
expression
in response to extracellular stimuli.
When these changes occur normally, cells pass through developmental
checkpoints and eventually a mature T cell results. However when they occur abnormally, immunodeficiency,
autoimmunity or leukemogenesis may be the result. |
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Leukemia
Blood Cells |
Leukemia
Bone Marrow |
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are studying a gene, Ikaros, which plays an integral role in defining the
genes which are expressed within a developing T cell.
Ikaros is a nuclear zinc finger protein which plays a role in both
activation and repression of transcription.
Two mutant Ikaros mouse strains have been engineered which provide
strong evidence that Ikaros regulates T cell development and homeostasis.
One strain, Ikaros dominant negative (DN), expresses high levels of
a dominant negative Ikaros isoform as the result of deletion of Ikaros'
amino-terminal zinc finger domain.
The second, Ikaros null, contains no stable Ikaros protein and is
therefore null for Ikaros activity.
Mice which are heterozygous for the Ikaros dominant negative
mutation (DN+/-) and homozygous for the Ikaros null mutation (null-/-)
have severe defects in their T lineage cells as summarized below.
It
is particularly dramatic that these mice develop T cell leukemias
with 100% penetrance providing evidence that Ikaros is a tumor suppressor
gene for the T cell lineage. |
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The
molecular basis for the T cell abnormalities observed in the absence of
Ikaros has not yet been discovered. It is likely, however, that it is the
result of inappropriate decoding of extracellular signals. These signals
include those events that occur when a T cell receptor (TCR) encounters an
antigen in the context of the major histocompatibility complex (MHC). This
interaction is translated into changes in programs of gene expression
which lead to the developmental progression of a thymocyte or controlled
proliferation of a mature T cell. Before
a cell can turn on the expression of some genes and shut down the
expression of others, interactions between histones and DNA in chromatin
must undergo tremendous changes. Chromatin remodeling complexes, such as
the NURD (containing the ATPase Mi-2 and HDACs) and SWI/SNF (containing
the ATPase Brg-1) complexes, modulate the higher order structure of
chromatin which hinders or facilitates, respectively, the binding of
transcription factors. The findings that Ikaros interacts with the NURD
and SWI/SNF complexes suggest that, in the absence of Ikaros these
remodeling complexes may be inappropriately targeted, leading to
abnormalities in gene expression in Ikaros deficient T cells. |
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Scientific
Goals
1) To search
for genes regulated by Ikaros in order to define its role in
leukemogenesis and T cell development.
We are utilizing microchip gene array technology to compare
programs of gene expression in T cell populations from wild-type and
Ikaros mutant mice. The
results from these experiments will provide insight into the ordered
progression of gene expression which occurs as an immature thymocyte
develops into a mature T cell and as a normal T cell becomes malignant.
2) To restore
Ikaros function to Ikaros mutant T cells using a gene therapy approach.
The Ikaros gene encodes six Ikaros isoforms, three of which are
expressed at high levels in lymphocytes.
We would like to determine the function of each of these isoforms
in lymphocyte development and leukemogenesis by expressing them
individually at the hematopoietic stem cell level using retroviral
transduction of bone marrow from Ikaros null mice.
3)
To identify Ikaros gene mutations in human leukemias. Evidence from other laboratories has provided evidence that
Ikaros expression is abnormal in human leukemia cells.
We would like to perform a comprehensive examination of the genomic
Ikaros locus in leukemia cells using a technique known as single-stranded
conformation polymorphism (SSCP) analysis.
We will then determine how these mutations affect Ikaros function
using both in vitro and in vivo assays. These studies will define a new
molecular mechanism involved in leukemogenesis.
This, in turn, will lead to more specifically directed treatment
strategies and new therapeutic approaches. |
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Assistant Professor
Department of
Microbiology-Immunology
Northwestern University Medical
School
320 E. Superior St. Morton 6-654
Chicago, IL 60613
Telephone:(312)503-3075
Fax: (312)503-1339
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