Kreeger:Research

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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, 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.

Bioengineering 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 hope to determine which interactions drive endometriosis and identify therapeutic targets.

Cellular Decision-Making Processes in Wound Healing and Angiogenesis
In both in vivo and in vitro environments, cells are exposed to numerous extracellular stimuli that regulate their function, such as extracellular matrix proteins, growth factors, and mechanical forces. The nature of these cues and their subsequent interpretation by cells is complex; sometimes these cues work in concert to instruct cells to perform a certain function, and other times these cues are conflicting. We aim to better understand how cells “decide” what cues to follow in this complex environment, particularly in the context of dermal wound healing and angiogenesis. This work will also be combined with computational modeling (collaboration with Prof. Pam Kreeger) to predict cell behavior in untested environments. Such efforts to better understand and predict cellular decision-making processes is important in not only informing the construction of environments that allow greater control over cell behavior, but also in understanding native physiological phenomena.


Funding
Funding for our research is provided by:
NSF CAREER award
NIH/NIGMS R01 (PI: KS Masters)
American Cancer Society Institutional Research Grant
UW-Madison Graduate School

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