Targeting the Estrogen Pathway for the Prevention and Treatment of LAM

靶向雌激素途径预防和治疗 LAM

• 批准号: 8474830
• 负责人: Jane Yu
• 金额: $ 40.58万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-09 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8474830
• 关键词: Address; Affect; Animals; Anoikis; BIM Bcl-2-binding protein; Benign; Bortezomib; CI-1040; Cause of Death; Cell Survival; Cells; Clinic; Data; Development; Disease; Disease Progression; Estrogens; Event; Female; Goals; Histologic; Human; In Vitro; Lead; Lung; Lung Transplantation; Lymphangioleiomyomatosis; Lymphatic; MAP Kinase Gene; MAP2K1 gene; MEKs; Mediator of activation protein; Metastatic Neoplasm to the Lung; Modeling; Molecular; Mutation; Neoplasm Circulating Cells; Neoplasm Metastasis; Null Lymphocytes; Pathogenesis; Pathway interactions; Patients; Prevention; Proteasome Inhibitor; Proteomics; Role; Series; Signal Transduction; Smooth Muscle Myocytes; Stromal Cells; TSC2 gene; Testing; Therapeutic; Woman; base; human TSC2 protein; in vivo; in vivo Model; inhibitor/antagonist; novel strategies; prevent; public health relevance; tumor xenograft; young woman

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)：这项建议集中在淋巴管肌瘤病(LAM)发病机制的分子机制，这是一种影响年轻女性的破坏性疾病。LAM几乎只影响女性的原因还没有明确界定。我们发现，雌激素促进静脉注射TSC2缺失的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节蛋白的细胞的存活，从而允许LAM细胞在肺和淋巴管中积聚。为了解决这一假设，我们提出了三个具体的目标：目的1.确定雌激素促进Tuberin缺陷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交互介体)是雌激素促进的存活的介体的假设，并确定在雌激素处理的ELT3细胞中BIM水平升高的信号事件。目的2.确定雌激素在体外和体内是否能增强LAM来源的细胞的存活。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是否在体外促进LAM来源的细胞在分离或附着条件下的存活，并确定E2是否促进LAM来源的细胞在体内的存活和/或转移。目的3.确定抑制MEK1/2和ER是否能逆转ELT3细胞已建立的肺转移。我们将确定靶向MEK1/2或ER(阻止或诱导E2诱导的ELT3细胞肺转移的进一步进展或消退)。我们将使用现代蛋白质组学方法确定ELT3细胞依赖于E2存活的其他分子决定因素。