This proposal is focused on the molecular mechanisms underlying the pathogenesis of lymphangioleiomyomatosis (LAM), a devastating disease affecting young women. The reasons that LAM affects women almost exclusively are not yet clearly defined. We have discovered that estrogen promotes the survival and lung colonization of intravenously injected Tsc2-null ELT3 cells. Our central hypothesis is that estrogen promotes the survival of tuberin-deficient cells, thereby allowing LAM cells to accumulate in the lungs and lymphatics. To address this hypothesis, we propose three Specific Aims:
Aim 1. To identify the molecular mechanisms through which estrogen enhances the survival and metastasis of tuberin-deficient cells. We will test the hypothesis that Bim (Bcl-2 interacting mediator of cell death) is a mediator of estrogen-promoted survival and identify the signaling events that underlie the enhanced levels of Bim in estrogen-treated ELT3 cells.
Aim 2. To determine whether estrogen enhances the survival of LAM-derived cells in vitro and in vivo. We will determine whether E2 promotes the survival of LAM-derived cells in vitro in either detached or attached conditions using a novel approach to distinguish between LAM cells and stromal cells, and determine whether E2 enhances the survival and/or metastasis of LAM-derived cells in vivo.
Aim 3. To determine whether inhibition of MEK1/2 and ER( leads to a regression of established lung metastasis of ELT3 cells. We will determine whether targeting MEK1/2 or ER( prevents further progression or induces regression of E2-induced lung metastasis of ELT3 cells. We will identify additional molecular determinants of E2-dependent survival of ELT3 cells using a modern proteomic approach.

Public Health Relevance

Our long-term goal is to identify the molecular mechanisms that underlie the female predominance of LAM, and thereby facilitate the development of effective therapeutic approaches for the treatment of LAM.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098216-04
Application #
8474830
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Peavy, Hannah H
Project Start
2010-08-09
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$405,784
Indirect Cost
$170,164
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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