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Targeting the Estrogen Pathway for the Prevention and Treatment of LAM

靶向雌激素途径预防和治疗 LAM

基本信息

批准号：
9171443
负责人：
Jane Yu
金额：
$ 4.05万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-09 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9171443
关键词：
Targeting Estrogen Pathway Prevention Treatment

项目摘要

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.

描述（由申请人提供）：该提案的重点是淋巴管平滑肌瘤病（LAM）发病机制的分子机制，LAM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。我们已经发现雌激素促进静脉内注射的Tsc 2缺失ELT 3细胞的存活和肺定殖。我们的中心假设是，雌激素促进结核菌素缺陷细胞的存活，从而使LAM细胞在肺和淋巴管中积累。为了解决这一假设，我们提出了三个具体目标：目标1。确定雌激素增强结核菌素缺陷细胞存活和转移的分子机制。我们将测试的假设，即Bim（Bcl-2相互作用的细胞死亡的调解人）是一个调解员的雌激素促进生存和识别的信号事件，在雌激素处理的ELT 3细胞的Bim水平提高的基础。目标二。确定雌激素是否能提高体外和体内LAM衍生细胞的存活率。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是否在体外分离或附着条件下促进LAM衍生细胞的生存，并确定E2是否在体内增强LAM衍生细胞的生存和/或转移。目标3。为了确定抑制MEK 1/2和ER（1）是否导致ELT 3细胞的已建立的肺转移消退。我们将确定靶向MEK 1/2或ER是否阻止E2诱导的ELT 3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ELT 3细胞E2依赖性存活的其他分子决定因素。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Insulin growth factor binding protein 2 mediates the progression of lymphangioleiomyomatosis.

胰岛素生长因子结合蛋白2介导淋巴管平滑肌瘤病的进展。

DOI：
10.18632/oncotarget.16695
发表时间：
2017
期刊：
Oncotarget
影响因子：
0
作者：
Li,Xiangke;Liu,Xiaolei;Zhang,Linda;Li,Chenggang;Zhang,Erik;Ma,Wang;Fan,Qingxia;Yu,JaneJ
通讯作者：
Yu,JaneJ

Reply: hormonally targeted therapy for women with lymphangioleiomyomatosis.

答复：针对女性淋巴管平滑肌瘤病的激素靶向治疗。