Targeting the Estrogen Pathway for the Prevention and Treatment of LAM

描述（由申请人提供）：本提案的重点是淋巴血管平滑肌瘤病（LAM）发病机制的分子机制，这是一种影响年轻女性的毁灭性疾病。LAM几乎只影响女性的原因尚未明确界定。我们发现雌激素促进静脉注射Tsc2-null的ELT3细胞的存活和肺定植。我们的中心假设是雌激素促进了缺乏结核菌素的细胞的存活，从而使LAM细胞在肺部和淋巴管中积累。为了解决这一假设，我们提出了三个具体目标：目的：探讨雌激素促进结节素缺乏细胞存活和转移的分子机制。我们将验证Bim（细胞死亡的Bcl-2相互作用介质）是雌激素促进存活的介质的假设，并确定雌激素处理的ELT3细胞中Bim水平增强的信号事件。目标2。目的：探讨雌激素是否能提高lam源性细胞的体外和体内存活率。我们将使用一种区分LAM细胞和基质细胞的新方法来确定E2是否能促进LAM来源细胞在离体或附着条件下的体外存活，并确定E2是否能增强LAM来源细胞在体内的存活和/或转移。目标3。确定抑制MEK1/2和ER(是否会导致ELT3细胞肺转移的消退。我们将确定靶向MEK1/2或ER是否能阻止e2诱导的ELT3细胞肺转移的进一步进展或诱导其消退。我们将使用现代蛋白质组学方法确定e2依赖性ELT3细胞存活的其他分子决定因素。

DESCRIPTION (provided by applicant): 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.