Kreeger:Research

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'''Signaling Network Cross-Talk in Ovarian Cancer''' <br>
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Ovarian cancer is the 5th leading cause of cancer death in women. The high mortality rate is primarily due to the late stage at which ovarian cancer is typically found. Patients accumulate different mutations in their tumors during disease progression, making it impossible to define a blanket treatment for everyone. We are working to characterize a panel of ovarian cancer cell lines to capture this diversity and determine how cells respond to current drugs. By delineating molecular signatures that correspond to drug sensitivities we hope to better match patients to drugs and improve prognosis.  Additionally, our models will attempt to reconstruct the cross-talk between various pathways in the cell.  These models will be examined to determine signals that are most responsible for controlling proliferation, providing new drug targets for ovarian cancer.
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'''Cellular and Signaling Network Cross-Talk in Ovarian Cancer''' <br>
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[[Image:OVCA_project_overview.jpg|350px|right]]
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Ovarian cancer has a mortality rate of greater than 50%, primarily due to the late stage at which it is diagnosed. This late diagnosis complicates treatment - patients accumulate different mutations in their tumors and tumor cells receive a variety of stimuli from other cell types during disease progression, making it impossible to define a blanket treatment for everyone. We are working to address this complex scenario through several complementary approaches. First, we are characterizing a panel of ovarian cancer cell lines to capture this diversity and determine how cells respond to current drugs. By delineating molecular signatures that correspond to drug sensitivities we hope to better match patients to drugs and improve prognosis.  Secondly, we are examining cross-talk between signaling pathways in the tumor cell to determine signals that are responsible for controlling proliferation, providing new drug targets for ovarian cancer. Finally, in collaboration with [http://obgyn.wisc.edu/directory/detail.aspx?id=40 Prof. Manish Patankar] we are developing in vitro culture systems to study interactions between ovarian cancer tumor cells and other cells in the tumor microenvironment in order to identify new approaches to control tumor growth. <br>
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[[Image:KreegerEndo.jpg|200px|right]]
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'''Analysis of Cell-Cell Interactions in Endometriosis'''<br>
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Endometriosis is a chronic gynecological condition that affects 5-10% of women resulting in pelvic pain and infertility. In endometriosis, endometrial tissue is found outside of the uterus, attached to the ovaries, uterine ligaments, and virtually any other region of the body. This ectopic endometrium triggers local inflammation in response to cyclic changes in estrogen, resulting in severe pain. Despite its prevalence and significant impact on women’s health, relatively little is known about how the disease develops or how to intervene due to a lack of model systems. We are developing an in vitro model that incorporates the epithelial, stromal, and macrophage components of the disease in order to examine how cell-cell interactions impact disease progression. Using this system, we will examine interactions drive endometriosis and, in collaboration with [http://obgyn.wisc.edu/directory/detail.aspx?id=19 Dr. Dan Lebovic], identify therapeutic targets.<br>
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'''Estrogen and Phytoestrogen Interactions in Breast Cancer''' <br>
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'''Cellular Decision-Making Processes in Wound Healing and Angiogenesis''' <br>
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Estrogen receptor (ER) expression is one of the best determinants for therapeutic choice in breast cancer. However, the roles of the two ERs (ERα and ERβ) in estrogen signaling remain unclear. Additionally, there are conflicting studies about the impacts of plant-based estrogens, called phytoestrogens, on breast cancer progression. To address these questions, we will experimentally alter the levels of ERα and ERβ and follow cellular signals and responses to treatment with estrogens and/or phytoestrogens. Our models will be used to identify critical signaling mechanisms regulating estrogenic effects on proliferation in breast cancer, providing novel drug targets.
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Tissue engineers are working to develop methods to restore or improve tissue function, largely through a process of trial and error. In contrast, we are working to determine design principles to inform the creation of tissue engineering scaffolds. In collaboration with [http://openwetware.org/wiki/Masters Prof. Kristyn Masters] and [http://nitrolab.engr.wisc.edu/ Prof. Justin Williams], we are characterizing how keratinocytes and endothelial cells interpret, integrate, and respond to simple and complex combinations of microenvironmental cues. In particular, we are examining the link between environmental cues, the downstream signaling events that result, and cellular responses. By identifying this relationship, we will be able to identify combinations of stimuli that promote desirable behaviors such as increased migration for wound healing or increased tubule formation for angiogenesis.<br>
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'''Funding''' <br>
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NSF CAREER award<br>
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NIH/NIGMS R01 (PI: KS Masters)<br>
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American Cancer Society Research Scholars Grant<br>
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UW-Madison Graduate School<br>
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Thank you to [http://www.turnerbiosystems.com/ Turner Biosystems] for granting us a Veritas Microplate Luminometer

Current revision

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Cellular and Signaling Network Cross-Talk in Ovarian Cancer

Ovarian cancer has a mortality rate of greater than 50%, primarily due to the late stage at which it is diagnosed. This late diagnosis complicates treatment - patients accumulate different mutations in their tumors and tumor cells receive a variety of stimuli from other cell types during disease progression, making it impossible to define a blanket treatment for everyone. We are working to address this complex scenario through several complementary approaches. First, we are characterizing a panel of ovarian cancer cell lines to capture this diversity and determine how cells respond to current drugs. By delineating molecular signatures that correspond to drug sensitivities we hope to better match patients to drugs and improve prognosis. Secondly, we are examining cross-talk between signaling pathways in the tumor cell to determine signals that are responsible for controlling proliferation, providing new drug targets for ovarian cancer. Finally, in collaboration with Prof. Manish Patankar we are developing in vitro culture systems to study interactions between ovarian cancer tumor cells and other cells in the tumor microenvironment in order to identify new approaches to control tumor growth.

Analysis of Cell-Cell Interactions in Endometriosis

Endometriosis is a chronic gynecological condition that affects 5-10% of women resulting in pelvic pain and infertility. In endometriosis, endometrial tissue is found outside of the uterus, attached to the ovaries, uterine ligaments, and virtually any other region of the body. This ectopic endometrium triggers local inflammation in response to cyclic changes in estrogen, resulting in severe pain. Despite its prevalence and significant impact on women’s health, relatively little is known about how the disease develops or how to intervene due to a lack of model systems. We are developing an in vitro model that incorporates the epithelial, stromal, and macrophage components of the disease in order to examine how cell-cell interactions impact disease progression. Using this system, we will examine interactions drive endometriosis and, in collaboration with Dr. Dan Lebovic, identify therapeutic targets.

Cellular Decision-Making Processes in Wound Healing and Angiogenesis
Tissue engineers are working to develop methods to restore or improve tissue function, largely through a process of trial and error. In contrast, we are working to determine design principles to inform the creation of tissue engineering scaffolds. In collaboration with Prof. Kristyn Masters and Prof. Justin Williams, we are characterizing how keratinocytes and endothelial cells interpret, integrate, and respond to simple and complex combinations of microenvironmental cues. In particular, we are examining the link between environmental cues, the downstream signaling events that result, and cellular responses. By identifying this relationship, we will be able to identify combinations of stimuli that promote desirable behaviors such as increased migration for wound healing or increased tubule formation for angiogenesis.


Funding
NSF CAREER award
NIH/NIGMS R01 (PI: KS Masters)
American Cancer Society Research Scholars Grant
UW-Madison Graduate School

Thank you to Turner Biosystems for granting us a Veritas Microplate Luminometer
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