Wnt-responsive adrenocortical cells in organ maintenance and cancer

Wnt 反应性肾上腺皮质细胞在器官维护和癌症中的作用

• 批准号: 7781531
• 负责人: GARY D. HAMMER
• 金额: $ 30.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7781531
• 关键词: Adrenal Cortex; Adrenal Gland Cancer; Adrenal Glands; Adrenocortical carcinoma; Binding Sites; Cancer cell line; Cells; Data; Differentiation and Growth; Disease; Exhibits; Future; Gene Activation; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Genome; Genomics; Growth; Health; Human; In Vitro; Laboratories; Maintenance; Malignant Neoplasms; Malignant neoplasm of adrenal cortex; Mediating; Molecular; Molecular Target; Mus; Nuclear Receptors; Oncogenic; Organ; Pathway interactions; Patients; Population; Role; SF1; Sampling; Signal Pathway; Signal Transduction; System; Therapeutic Intervention; Tumor Cell Line; Tumorigenicity; base; cell transformation; effective therapy; in vivo; mouse model; novel; public health relevance; transcription factor; tumorigenesis

DESCRIPTION (provided by applicant): The long range objective of our laboratory is to understand the cellular and molecular mechanisms by which signaling pathways and downstream transcription factors coordinate the specification of adrenocortical cells within the adrenal gland in health and disease. Our strategy for this proposal is to focus on the mechanism and consequences of Wnt-mediated activation of gene expression in adrenal cancer. Based on our preliminary data, we hypothesize that dysregulated Wnt/?-catenin signaling in adrenocortical subcapsular cells induces aberrant target gene activation by the nuclear receptor, steroidogenic factor 1 (SF1), and ultimate oncogenic transformation of cells within this population. Our specific aims are therefore directed towards a systematic characterization of the mechanisms by which Wnt/?-catenin target genes control the normal and dysregulated growth and differentiation of the adrenal cortex. To that end we propose to determine whole genome targets of Wnt-mediated SF1 transcription in adrenocortical carcinoma (ACC) in both human patients and mice and to define the role of a subset of these target genes in adrenal cortical growth maintenance and cancer in vitro and in vivo. We believe that the studies proposed here will provide the framework for understanding the role of Wnt/?-catenin signaling in adrenocortical growth maintenance and cancer and lay the groundwork for future targeted therapy. PUBLIC HEALTH RELEVANCE: Adrenal cancer is an incredibly rare and routinely fatal disease with few effective treatments. Understanding the cellular and genetic basis for the disease is predicted to provide novel cellular and molecular targets for therapeutic intervention. This proposal aims to elucidate the mechanism and consequences of Wnt-mediated activation of gene expression in adrenal cancer. Using cellular systems and mouse models together with genomic approaches in mouse and human adrenocortical carcinoma samples, we aim to characterize the mechanisms by which Wnt/?-catenin signaling participates in normal adrenal growth maintenance and cancer. Specifically, in these studies we will determine whole genome targets of Wnt-mediated Sf1 transcription in adrenocortical carcinoma (ACC) in human patients and mice and to define the role of a subset of these target genes in both normal growth and cancer of the adrenal cortex. Future efforts are predicted to focus on therapies that target this pathway and downstream genes that are found in the course of these studies.

描述（由申请人提供）：我们实验室的远程目标是了解细胞和分子机制，通过这些机制，信号通路和下游转录因子协调了健康和疾病中肾上腺内肾上腺皮质细胞的规范。该提案的策略是关注Wnt介导的基因表达激活在肾上腺癌中的机制和后果。基于我们的初步数据，我们假设在肾上腺皮质下细胞中的Wnt/？ - catenin信号传导失调会诱导核受体，类固醇生成因子1（SF1）的异常靶基因激活，并在该种群中诱导细胞的最终致癌性转化。因此，我们的具体目标是针对Wnt/？ - catenin靶基因控制正常和失调的肾上腺皮质生长和分化的机制的系统表征。为此，我们建议确定人类和小鼠肾上腺皮质癌（ACC）中Wnt介导的SF1转录的整个基因组靶标，并确定这些靶基因在肾上腺皮质生长维持和体外和体内癌症中的一部分的作用。我们认为，这里提出的研究将为了解Wnt/？ - catenin信号传导在肾上腺皮质增长和癌症中的作用提供框架，并为未来的靶向治疗奠定基础。 公共卫生相关性：肾上腺癌是一种非常罕见的，常规的致命疾病，几乎没有有效的治疗方法。预计了解该疾病的细胞和遗传基础可为治疗干预提供新颖的细胞和分子靶标。该建议旨在阐明Wnt介导的基因表达激活在肾上腺癌中的机制和后果。使用细胞系统和小鼠模型以及小鼠和人类肾上腺皮质癌样品中的基因组方法，我们旨在表征Wnt/？ - catenin信号传导参与正常肾上腺生长维持和癌症的机制。具体而言，在这些研究中，我们将确定人和小鼠肾上腺皮质癌（ACC）中Wnt介导的SF1转录的整个基因组靶标，并确定这些靶基因在肾上腺皮质正常生长和癌症中的子集的作用。预计未来的努力将重点放在针对这些研究过程中的这种途径和下游基因的疗法上。