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Uterine-Specific Knockout of TSC-2: A Mouse Model for Lymphangioleiomyomatosis (LAM)

Principal Investigator: HAMMES, STEPHEN R
Institution Receiving Award: ROCHESTER, UNIVERSITY OF
Program: TSCRP
Proposal Number: TS110032
Award Number: W81XWH-12-1-0496
Funding Mechanism: Exploration-Hypothesis Development Award
Partnering Awards:
Award Amount: $154,500.00


PUBLIC ABSTRACT

Lymphangioleiomyomatosis (LAM) is a lung disorder that consists of multiple "smooth muscle-like" tumors that progressively grow until they interfere with normal lung function. Nearly 80% of patients with LAM will have a lung collapse, more than 30% will develop fluid in their lungs, and a large number of patients will require lung transplantation at some point in their lives. Even after transplantation, the majority of patients eventually find that the tumors return. In addition to the suffering that accompanies the progressive suffocation due to the loss of functional lung, the ultimate fate for a large number of patients is death.

The goal of the research proposed here is to find a cure for LAM. Interestingly, LAM has some unusual properties that, if better understood, could be used against it when it comes to treatment. First, LAM is found almost exclusively in women, suggesting that the LAM tumors may originate from or be stimulated by factors found primarily in women. Second, LAM tumors seem to grow during pregnancy or when women are on birth control pills, suggesting that female hormones such as estrogen or progesterone might be driving LAM tumor growth (consistent with LAM being found in women). Third, LAM tumors look like smooth-muscle cell tumors of the uterus, suggesting that they might be related to other common uterine tumors such as leiomyomas (often called "fibroids"). Like LAM lesions, uterine leiomyomas appear to be hormone-sensitive and are worse during pregnancy and when women are on birth control pills. Finally, LAM tumors contain mutations in one of the two tuberous sclerosis (Tsc) genes, which are the genes that are altered in the disease "tuberous sclerosis."

Putting all of this information together, we propose that LAM tumors are basically uterine leiomyomas that have been made more aggressive through activation of the Tsc gene. This uterine origin would explain why LAM is found almost exclusively in women and why it is sensitive to steroids. Our plan is to shut off Tsc signaling exclusively in the uterus of a mouse and then see if these mice develop uterine or lung tumors that resemble LAM. Preliminary data suggest that the uteri of these mice are growing out of control, so now we are ready to examine them more closely and to study hormone-dependent growth in a test tube and in live animals. Our hope is to use these mice as a model for LAM that will allow us to develop novel strategies to both detect and treat LAM.