Pathology Resident Research Electives
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The goal of this Pathology Resident Research Elective website is to maximize the opportunities for residents and fellows
to connect with faculty mentors and current research projects. In combination with a series of faculty presenations
focused on resarch projects currently available and suited to time constraints, it is our hope that trainees will be
able to easily identify mentors and projects that inspire them to pursue further research.
In addition to the electives described on this page, Department of Pathology researchers are also presenting summaries
of their projects at Didactic Lectures on first and third Tuesdays beginning
in September.
If a resident is interested in participating in a research elective, he/she should contact the project mentor and Residency
Program Director. The resident needs to complete the Elective Form found on the Residents'
IWeb. Once the form is completed, it goes to the Residency Manager. The deadline for submitting elective requests is
May 15 for the upcoming academic year.
ELECTIVES
Mentor: Charles Alpers, MD
Elective Length: 6 weeks
Mouse models that reliably reproduce the features of human glomerulonephritis have traditionally been difficult to
develop. The value of such models is heightened by the ability to utilize murine species for gene targeting and
transgene insertion in order to test the roles of specific mediator molecules in the initiation and progression of
renal disease. We have recently developed a transgenic mouse model in which mice predictably develop cryoglobulinemia
and immune complex mediated membranoproliferative glomerulonephritis as a result of cryoglobulin deposition. The
features of this model are nearly identical to those that occur in human cryoglobulinemic glomerulonephritis and
membranoproliferative glomerulonephritis. Since cryoglobulinemia is a systemic disease, the mice also develop a
noteworthy and striking pneumonitis, dermatitis, and hepatitis. Damage in each of these organs may serve as a useful
model to study human disease in these organs related to cryoglobulinemia or other immune complex deposition processes,
as it has in the kidney. This project is ideally suited for a pathology resident who is looking to use a mouse model
to understand pathologic phenomena that occur in human diseases that routinely are encountered in an academic
diagnostic pathology setting. The fellow would have the opportunity to use routine diagnostic modalities such as
histology, immunofluorescence microscopy, and electron microscopy to characterize further the pathology in these
extrarenal organ systems, particularly lung and skin. The laboratory has available a considerable array of resources
to perform immunohistochemical and in situ hybridization analysis for gene and protein expression and cell phenotypes
that would help characterize the pathology of these lesions. The ultimate goal would be to characterize a suitable
model for further studies of mechanisms of lung and skin injury. The resident would be able to take advantage of the
various gene knockouts and transgenes that have already been inserted into these animals to modify expression of key
mediator molecules, such as Fc receptors and mediator of the complement system, to develop and test mechanistic
hypotheses.
Mentor: Charles Alpers, MD
Elective Length: 6 weeks
This would represent a smaller project within the overall structure of the six-month project as described. Smaller
projects that could be readily approached by pathology residents using their pathology skills include a comparative
study of the skin and lung and liver lesions of our transgenic mice, which are transgenic for thymic stromal
lymphopoietin (TSLP) under the control of an Ick promoter, with TSLP transgenic mice under the control of other
promoters, developed by our collaborator Steve Ziegler at the Benaroya Research Institute, which have somewhat
different pathology as a result of this molecular modification. A more restricted study of the expression of
specific mediator molecules in these organs using immunohistochemistry and in situ hybridization approaches are also
readily available (e.g., expression of specific chemokines and chemokine receptors, expression of specific growth
factors such as vascular endothelial growth factor, connective tissue growth factor, etc.)
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Mentor: Karin E. Bornfeldt, PhD
Elective Length: 6 weeks
Diabetes accelerates cardiovascular disease caused by atherosclerosis. We are studying the mechanisms of diabetes-
accelerated atherosclerosis using a transgenic mouse model and isolated vascular cells (smooth muscle cells and
macrophages). The goal of this project is to investigate the extent of apoptosis in atherosclerotic plaques from
diabetic and non-diabetic mice by using immunohistochemical methods. Apoptosis of macrophages is believed to contribute
to plaque rupture, and the acute clinical manifestations of atherosclerosis.
Mentor: Karin E. Bornfeldt, PhD
Elective Length: 6 months
Diabetes accelerates cardiovascular disease caused by atherosclerosis. We are studying the mechanisms of diabetes-
accelerated atherosclerosis using a transgenic mouse model and isolated vascular cells (smooth muscle cells and
macrophages). Common fatty acids are believed to contribute to atherosclerotic plaque progression in diabetes, which
is often associated with hypertriglyceridemia. The goal of this project is to investigate regulation of enzymes
required for fatty acid metabolism long-chain acyl-CoA syntheses in macrophages isolated from non-diabetic and
diabetic mice. Several different isoforms of acyl-CoA synthetase will be detected by RT-PCR and Western blot analyses.
[TOP]
Mentors: Nelson Fausto, MD, Jean Campbell, PhD & Matthew Yeh, MD PhD
Elective Length: 6 weeks or 6 months
Liver fibrosis and cirrhosis are the main components of chronic liver disease of various etiologies, including viral
hepatitis, alcoholic liver disease and non-alcoholic fatty liver disease. All of these chronic conditions have
increased risk for the development of hepatocellular carcinomas. Despite much progress, the mechanisms of liver
fibrosis, which involve the activation of liver stellate cells, are still largely unknown. Similarly, the mechanisms
that determine the chronicity of the lesions and the transition to carcinomas are not well understood. One of the
major difficulties in studying these processes is the lack of appropriate animal models that mimic liver fibrosis that
occurs in patients with chronic liver disease. We have developed a mouse model involving the expression of a
newly-identified growth factor (PDGF-C) in which activation of stellate cells leading to fibrosis occurs within 4
weeks after brth. As the fibrosis progresses, practically all animals develop hepatocyte dysplasia and eventually
hepatocellular carcinomas. Residents participating in this work will become familiar with both the complex
morphological changes associated with fibrosis andthe development of tumors, and the molecular mechanisms that may be
responsible for these conditions. The overall goal of the work is to elucidate the pathogenesis of liver fibrosis and
its evolution into neoplasia, using an animal model that reproduces the main features of the human disease.
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Mentors: Ingegerd Hellström, MD & Karl Erik Hellström, MD
Elective Length: 6 weeks
The Drs. Hellström were involved in some of the early discoveries in tumor immunology. More recently they have
focused their work in two areas: serum-based tumor diagnostics (led by Dr. Ingegerd Hellström) and tumor vaccines
(led by Dr. Karl Hellström). The diagnostic studies (first published in PNAS 96,11531,1999) have demonstrated that
soluble molecules belonging to the mesothelin family can be detected in sera and malignant effusions by using a
Sandwich ELISA. The ELISA is very useful for diagnosis of mesothelioma (Lancet 362,1612,2003) and complements CA125
to facilitate diagnosis of ovarian carcinoma (Gynecol. Oncol., in press 2004). This project will perform diagnostic
studies, applying serum assays of the mesothelin family for clinical use.
Mentors: Ingegerd Hellström, MD & Karl Erik Hellström, MD
Elective Length: 6 months
Immunotherapeutic studies have been initiated in collaboration with Drs Kiviat, Lieber and Disis at the UW with the
goal of developing a therapeutically useful vaccine for cervical carcinoma, continuing and expanding work done
collaboratively with Dr Disis' group on carcinomas of the breast and ovary.
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Mentor: Robert F. Hevner, MD PhD
Elective Length: 6 weeks
Our lab studies development of the cerebral cortex, including neuron proliferation, migration, differentiation, and
axon guidance. In addition, we have projects to study human cortical malformations and brain tumors. For more
information on our research, visit our web site. This project will research
proliferation of astrocytes in reactive (non-neoplastic) conditions. A recurring problem in neuropathology is whether
significant expession MIB-1 (a proliferation marker) indicates neoplasia, or can occur in the setting of reactive
astrocytosis after trauma or surgery. We have used double labeling for GFAP (astrocyte marker) and MIB-1 in well-
documented cases or reactive astrocytosis, and preliminary evidence suggests that reactive astrocytes can express
MIB-1. This project will involve studying a larger series of cases, and cell counting to determine MIB-1 labeling
index values in reactive astrocytosis. This project will have a high likelihood of publication, and would be a fairly
high impact study in neuropathology.
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Mentor: Marshall Horwitz, MD PhD
Elective Length: 6 weeks
The goal of the laboratory is to elucidate the molecular mechanisms of leukemia, lymphoma, and bone marrow failure
through the study of heritable disorders predisposing to such illnesses. To date we have identified genes responsible
for human cyclic neutropenia (ELA2, encoding neutrophil elastase), canine cyclic neutropenia (AP3B1, encoding a
subunit of the AP3 intracellular transporter), human severe congenital neutropenia (ELA2 and also the oncogenic
transcription factor Gfi1) and have confirmed the identity of a gene responsible for familial platelet disorder with
predisposition to leukemia (Runx-1, encoding the transcription factor AML1). We have mapped presumptive loci for
familial acute myelogenous leukemia to chromosome 16q and for familial Hodgkin's disease to the pseudoautosomal regions
of the sex chromosomes. Molecular biological investigations have focused on the intracellular trafficking of
neutrophil elastase, which appears to be a cargo protein for the adaptor complex subunit encoded by AP3B1, as well as
on the transcriptional regulation of ELA2 by Gfi1 and AML1.
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Mentor: Qubai Hu, MD PhD
Elective Length: 6 months
My research goal is to understand the molecular mechanisms that underlie the pathogenesis of dementias of the
Alzheimer type (DAT). Mutations found in a gene coding for the beta-amyloid precursor protein (APP) cause early onset
DAT. Aberrant processing and function of APP are thought to be the underlying mechanism. My focus has been on the
proteins binding to the APP intracellular domain (AICD) (especially adaptor protein FE65) and their roles in
modulation of APP functions. Strong FE65-AICD interactions have evolved in human lineage, but its impact on APP
function has been unclear. My recent evidence suggests that FE65 may be an intracellular mediator for modulation of
APP function via a cell-cell/cell-substrate signaling cascade. Current projects attempt to identify what extracellular
cues and intracellular molecules trigger/enhance the signaling cascade. These experiments include gene expression,
protein interaction and processing, and signal transduction.
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Mentor: Raj Kapur, MD PhD
Elective Length: 6 months
Physiological studies of acetylcholine release from enteric neurons in normal and mutant animals.
One of our mouse models is due to disruption of protein kinase A (PKA) activity in enteric ganglion cells. The mice
die at weaning with severe duodenal and proximal jejunal distention. Current models of PKA function in enteric
ganglion cells suggest that the enzyme facilitates cholinergic neurotransmission and we can rescue the animals with
neostigmine treatment. We would like to develop an assay to measure acetylcholine production by intestinal organ
preparations (others have done this) to determine whether less neurotransmitter is released from the ganglion cells
of our mice. These studies will require manual microdissection of intestinal wall to isolate the myenteric plexus (we
can teach this) and use of a physiological buffer system to control pH and temperature while data samples are
collected. Acetylcholine will be measured by either a fluorometric assay or tandem mass spectroscopy (using resources
available in the clinical laboratory at CHRMC).
Mentor: Raj Kapur, MD PhD
Elective Length: 5 weeks
Physiological studies of peristalsis in normal and mutant animals.
Isolated segments of intestine are capable of peristaltic activity for hours in an appropriate in vitro system.
Basically, a pellet of clay is placed in the oral end of an intestinal segment and it is translocated to the anal end.
We would like to establish such a system to compare peristalsis in two of our mutant models with control intestinal
segments.
Mentor: Raj Kapur, MD PhD
Elective Length: 5 weeks
Establishing normative data for human and/or murine ganglion cell density.
Counting neurons in the gut wall is a big deal, since potential causes of intestinal dysmotility are hypo- and
hyperganglionosis. It sounds simple, but actually is challenging when you consider all of the variables that can
affect such counts (e.g., section thickness, morphological criteria to call a cell a neuron, orientation of the
section, age of patient, location along GI tract). The availability of neuron-specific antibodies (e.g., Hu C/D) may
make it easier to count neurons, but we need normative data to make meaningful comparisons. A relatively simple and
very useful study would collect such data using simple microscopy and with the explicit goal of developing an approach
that any pathologist can use without much practice. We also may be able to think of automated techniques to achieve
the same end (e.g., flow cytometry).
[TOP]
Mentor: George M. Martin, MD
Elective Length: 5 weeks
Expression of lamin A/C mutations in cultured cells
Mutations at the Lamin A locus are responsible for the Hutchinson Gilford Progeria Syndrome and for a subset of
Atypical Werner Syndrome patients. Dominant mutations have also been introduced into wild type cells. The lab has
documented a number of molecular, biochemical and nuclear pathologies in these mutant cells. RNAi constructs have been
expressed, with preliminary evidence that at least one such construct can ameliorate the impact of these putative
dominant negative mutations. These phenotypes have to be explored in greater detail, including immunocytochemical
studies suitable for short term projects by residents. Reference: L Chen et al., Lancet 362:440, 2003
Mentor: George M. Martin, MD
Elective Length: 5 weeks
Immunocytochemical co-localization studies of processed polypeptides derived from the beta amyloid precursor
protein and a major APP-binding protein known as FE65.
The beta amyloid precursor protein is of central importance in the pathogenesis of dementias of the Alzheimer type.
Its processing and the cytological localizations of its processed polypeptides and their functions are influenced by a
complex network of associated proteins. To further clarify these associations, we are carrying out a systematic series
of co-localization studies using confocal microscopy. Reference: SL Sabo et al., J Neurosci 23:5407, 2003
Mentor: George M. Martin, MD
Elective Length: 6 months
Assay of telomere lengths in DNA from peripheral blood cells
We are in the process of establishing a quantitative PCR method for the determination of mean telomere lengths in
blood from subjects enrolled in the National Long Term Care Survey, a population-based study of all US residents 65
years of age and older. Medicare records and scores for functionality are available from all subjects. Attempts will
be made to confirm and extend recent evidence that these assays are predictive of susceptibility to cardiovascular and
infectious diseases and to the probability of survival. Reference: RM Cawthon et al., Lancet 361:393, 2003
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Mentor: Arthur (Dusty) Miller, PhD
Elective Length: 6 months
Jaagsiekte sheep retrovirus (JSRV) causes adenocarcinoma of the lung in sheep and goats, while another closely related
retrovirus, enzootic nasal tumor virus (ENTV), causes tumors originating in the nasal epithelium of sheep and goats.
We are interested in the mechanisms of tumor induction by these retroviruses in animals, and the possibility that
related viruses might be involved in some forms of human lung cancer. Recently we have developed a mouse model for
JSRV-induced lung cancer. This model will allow us to address several questions regarding the tissue specificity of
JSRV- and ENTV-induced disease, rates of and requirements for progression of tumors from adenomas to adenocarcinomas,
the mechanisms of oncogenesis, and interactions of other oncogenes with the viral envelope protein, the key viral
oncogene. These goals provide multiple possibilities for short-term projects of interest to students of pathology.
[TOP]
Mentor: Drs. Raymond J. Monnat, Jr., MD/Thomas J. Lawton, MD/Trisha N. Davis, PhD
Elective Length: 6 weeks
Many human breast carcinomas display evidence of chromosomal aneuploidy and missegregation. The cause of this may be
abnormalities in centrosome number or function. A previous collaborative project between the Davis lab in Biochemistry
and the Monnat lab in Pathology identified a new human centrosomal component, kendrin, that may be mutant in human
breast carcinomas (Flory MR, et al. Proc Natl Acad Sci USA. 97:5919, 2000). On the basis of this work the three
mentor labs have received an Army Breast Cancer grant to determine if mutations in this protein are prevalent in human
breast carcinomas and may be contributing to aneuploidy. In this elective, the trainee will work with Tom Lawton to
identify invasive breast cancer cases and retrieve blocks, and then work with the Davis lab to isolate tumor DNA and
PCR amplify and sequence portions of the human kendrin gene from tumor and control cell DNA. There may be an opportunity
to participate in ongoing proteomic work to characterize all of the human centrosomal protein components.
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Mentor: Thomas J. Montine, MD PhD
Elective Length: 6 weeks
The pathologic bases of age-related cognitive decline remain largely unknown although it is widely assumed that
processes that underlie Alzheimer disease (AD) are the major culprits. This project will test that hypothesis. The
Neuropathology Division is the core facility for all autopsies performed in the Adult Change of Thought (ACT) study,
a population-based study of age-related cognitive decline and incident dementia in King County, WA. Currently about
160 autopsies have been performed on ACT participants, all of whom have detailed psychometric data. The goal of this
project will be to evaluate all of the autopsies using standardized criteria for AD, Lewy body disease, and vascular
damage to brain and then correlate these findings with changes in psychometric data.
Mentor: Thomas J. Montine, MD PhD
Elective Length: 6 weeks
Prostaglandin (PG) E2 is the major PG produced in brain where it potently modulates physiologic and pathophysiologic
processes. PGE2 is different from other eicosanoids in that it signals via 4 different, often functionally
antagonistic, cell surface receptors called EP1 to EP4. The distribution of these receptors in human brain and
expression in diseases of brain is unknown. We have recently obtained 3 mouse monoclonal antibodies to some EP
receptor subtypes. The goal of this project is to map expression of these proteins by immunohistochemistry in human
brain regions as well as survey neuropathologic conditions.
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Mentor: W. Tony Parks, MD
Elective Length: 6 weeks
The sorting nexins are a large family of vesicle-associated proteins involved in the intracellular trafficking of
plasma membrane receptors. Loss of at least one of these (SNX1) may play a role in the development of cancer. While
a number of the sorting nexins appear to function together in large multimolecular complexes, preliminary data
unexpectedly suggest that these proteins do not always reside within the same cell types. The cellular distributions
of these proteins have not yet been examined in detail. This project will involve staining mouse and human tissues
with antibodies against the sorting nexins to delineate the expression patterns for these proteins.
Mentor: W. Tony Parks, MD
Elective Length: 6 weeks
PX domain containing proteins typically localize to endosomal structures such as the early endosome and the lysosome.
We have identified one PX domain containing protein, SNX23, that appears to localize to the Golgi. Moreover, this
large protein has a kinesin motor domain, suggesting that it functions in tethering Golgi vesicles to the microtubular
network. This is the first known PX domain containing protein to combine these functions. We currently have only a
partial construct for the protein, and this project will involve cloning the full-length molecule, expressing it in
cells, determining its localization, and (time permitting) examining its function.
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Mentor: Kelly Smith, MD PhD
Elective Length: 6 weeks
Lipocalin 2 is an acute phase protein that binds bacterial siderophores and protects hosts against bacterial infections.
Lipocalin 2 has also been implicated in a vast number of biological processes, such as iron homeostasis, implantation,
kidney development, and cancer. We have made polyclonal antibodies to human and mouse lipocalin 2. The goal of this
project is to survey the expression of lipocalin 2 in normal and pathologic tissues.
Mentor: Kelly Smith, MD PhD
Elective Length: 6 months
We have generated a knockout mouse that is deficient in lipocalin 2 expression and determined that this mouse is more
susceptible to specific bacterial infections. Lipocalin 2 has also been found to be upregulated during acute toxic
and ischemic renal injury. The goal of this project is to assess the role of lipocalin 2 in different forms of kidney
disease. This study will use the knockout mice, and polyclonal antibodies to assess the role of lipocalin 2 in
regulating acute renal injury in the mouse.
Mentor: Kelly Smith, MD PhD
Elective Length: 6 weeks-6 months
The role of innate immunity in Salmonella infection. We are studying oral Salmonella infection in
different strains of mice. One mouse strain develops chronic active enteric inflammation that resembles inflammatory
bowel disease. We are also using knockout mice in this model to determine the role of specific innate immune genes
in controlling the bacterial infection. This study will analyze the histopathology of disease in mice, and correlate
this information with additional data (bacterial burden, cytokine expression, genetics and immunohistochemistry).
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Mentor: Karen L. Swisshelm, PhD
Elective Length: 5 weeks
Our broad interests are breast cancer & tumor suppressor proteins and chromosome instability & cancer. For carcinoma(s)
of interest, using a monoclonal antibody against the tight junction protein, claudin 1, determine subcellular
localization of the protein as a function of stage/grade. Human subjects application required.
Mentor: Karen L. Swisshelm, PhD
Elective Length: 6 months
The retinoic acid receptor beta (RARb) gene is a member of the nuclear hormone receptor family and is considered a
tumor suppressor gene in a variety of carcinomas. A truncated isoform, RARb-prime, is expressed exclusively in breast
cancer cells compared to normal human mammary epithelial cells. This project would entail evaluating a newly
generated panel of monoclonal antibodies. Methods include: preparation of cell pseudoblocks, laser capture
microdissection, immunostaining, and Western analysis. These antibodies have possible clinical application. Outcome
from this project would likely lead to a publication. Human subjects in place.
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Mentor: Lawrence D. True, MD
Elective Length: 5 weeks
Analyze expression and distribution of specific proteins (that we have found differentially expressed in cancers of
different Gleason grade by RNA expression analyses) in prostate cancers of different grade and stage, with different
clinical outcome. The 3 biomarkers to first immunohistochemically study are CD10 (CALLA), CD26, and AMACR. We would
use formalin fixed samples from both the radical prostatectomies that I have sampled for such studies over 12 years
and samples from metastases collected in the Rapid Tissue Acquisition Prostate Cancer Necropsy Program.
Mentor: Lawrence D. True, MD
Elective Length: 5 weeks
Investigate immunohistochemical tools to differentiate flat and papillary bladder lesions. There is preliminary data
that differential expression of specific keratins and the distribution of keratin 7/keratin 20-positive cells can make
more certain the differentiation of CIS from reactive atypia. The clinical importance of ruling out CIS of the bladder
is profound. To date, the histologic differentiation has sometimes been problematic. (Former resident Dr. Angelic
Oviedo has previously worked with me on this topic, with Dr. Peter Rabinovitch, using flow cytometry).
Mentor: Lawrence D. True, MD
Elective Length: 5 weeks
Analysis of the robustness and reproducibility of quantitative immunohistochemistry. Specifically, different scales of
reporting biomarker immunostaining of prostate tissue samples will be compared with respect to reproducibility,
efficiency, and predictiveness of clinical outcome. (Note, at a time when $100,000 + machines are being marketed to
“quantify” immunostains, it is important to show that the results these machines obtain provide more value than
optical assessments of immunostains). As a corollary project, prostate cancer cell lines expressing different levels
of such antigens as PSA will be analyzed.
Mentor: Lawrence D. True, MD
Elective Length: 5 weeks
(This project will probably be undertaken by resident Dr. Dan Toweill).
Survey practicing pathologists, urologists and oncologists for use of the College of American Pathologists Practice
Guidelines for reporting prostate cancer in prostatectomy specimens. The survey would address (to the pathologists)
questions such as whether and how they report potentially problematic features such as margin status and tumor volume,
and (to the urologists) usefulness and clinical value of such pathologic parameters as tumor volume and extent of
margin positivity.
Mentor: Lawrence D. True, MD
Elective Length: 5 weeks or 6 months
Characterize the transcriptome of a histologically defined cell population of the prostate, using laser microdissection
to isolate the specific cells. For example, the transcriptome of stromal cells and transition zone (the site of Benign
Prostatic Hypertrophy) is expected to differ from that of the peripheral zone (in which BPH nodules do not occur).
(We have done preliminary work with Dr. Tom Norwood and Pete Nelson).
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Mentor: Jing Zhang, MD PhD
Elective Length: 6 weeks
Aggregation of alpha-synuclein has been implicated in the pathogenesis of Parkinson’s disease and dementia with Lewy
bodies. Using quantitative proteomics, we have identified numerous novel proteins that are associated with alpha-
synuclein in the setting of neuronal degeneration. The goal of this project is to study which of these proteins is
associated with Lewy bodies by immunohistochemistry in human brain.
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Residency Webpage Editor: Michelle Rickard, Residency Manager