An Innovative Model System of Cell Invasion in TSC/LAM to Uncover New Drug Targets and Therapies
Abstract
In order to better understand the underlying reasons for Tuberous Sclerosis Complex (TSC) symptoms and to test potential new therapies, laboratory scientists can use cell or animal models. Cell studies allow for rapid analysis and high-throughput drug testing, but don’t reflect the true body environment of the TSC cysts. Animal models give a more realistic impression of how effective a drug is, but they are expensive, time-consuming, and have associated ethical issues. Therefore, a major challenge in TSC research is to develop cell models that are more representative of the body to study disease pathology. In the case of lymphangioleiomyomatosis (LAM), the movement of TSC cells through the body to form lung cysts cannot be replicated in standard cell culture and animal models are experimentally restrictive. This project establishes an innovative world-leading cell circulating model of LAM that better mirrors the LAM disease process and can be easily manipulated experimentally to more rapidly accelerate the search for effective therapies. In this new system, LAM cells are pumped through cell-lined hollow fibers to mimic blood flow through small blood vessels and are then monitored for their ability to move from the “blood” into an external space containing lung cells. By studying the genes and proteins switched on in the cells that migrate into the “lung” and comparing these to those switched on in the cells that fail to migrate through, we can get a better understanding of how LAM cells colonize the lung. Importantly, this knowledge gained will allow us to test new drugs to block LAM cell migration to the lung. This project addresses several priority areas in TSC research. It improves TSC disease models by establishing a more realistic cell model of LAM that could become a key tool to explore LAM biology and has the potential to accelerate new treatments from the laboratory into clinical use. By studying the genes and proteins involved in LAM cell movement, we will gain a deeper knowledge of TSC signaling pathways and the consequences of TSC deficiency. Finally, the model will establish a long-term platform to screen therapeutic drugs for LAM patients, thus facilitating the testing of new LAM therapies, while the genes and proteins characterized in this project will aid biomarker research. The research will help LAM patients and contribute to improved treatment options for TSC, through a better understanding of the biology of LAM and by providing a new model to test better therapies. Additionally, the system may translate to cancer patients at risk of metastatic disease. In addition, the study of circulating cells in this system may allow new biomarkers to be identified that would improve diagnosis of LAM in TSC patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910248
Entities
People
- Elaine Dunlop
Organizations
- Cardiff University
- United States Army