Nuclear Receptor Regulation of Epigenetics in Endocrine-Related Cancers

内分泌相关癌症表观遗传学的核受体调节

• 批准号: 10016237
• 负责人: Noelle Elizabeth Gillis
• 金额: $ 2.99万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-11 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016237
• 关键词: ATP phosphohydrolase; Address; Affect; Binding; Biological Process; Biology; Cell Line; Cells; ChIP-seq; Characteristics; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Clinical; Clinical Research; Data; Development; Endocrine; Environment; Epigenetic Process; Event; Exhibits; Family; Gene Expression; Gene Expression Regulation; Genetic Transcription; Genomics; Growth; Higher Order Chromatin Structure; Homeostasis; Hormones; Human; Individual; Ligands; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of thyroid; Mediating; Metabolism; Modeling; Mutation; Normal Cell; Nuclear Hormone Receptors; Nuclear Receptors; Pathway interactions; Patients; Phase; Phenotype; Physiological; Physiology; Play; Prognostic Marker; Receptor Signaling; Recurrence; Regulation; Reproduction; Research; Research Project Grants; Resistance; Role; SMARCA4 gene; Signal Transduction; Structure; THRB gene; Technical Expertise; Testing; Therapeutic; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormone Receptor Beta; Thyroid Hormones; Tissues; Training; Transcriptional Regulation; Translating; Tumor Suppressor Proteins; Tumor stage; Work; Xenograft procedure; base; cancer cell; chromatin remodeling; cofactor; combat; effective therapy; epigenetic regulation; genome-wide analysis; hormonal signals; hormone receptor-positive; hormone response element; hormone therapy; insight; interest; malignant endocrine gland neoplasm; member; mortality; novel; novel therapeutics; outcome forecast; programs; receptor binding; receptor function; recruit; response; restoration; synergism; targeted treatment; therapeutic target; therapy resistant; thyroid disruption; thyroid neoplasm; transcription factor; transcriptome; transcriptome sequencing; tumor; tumor growth; tumor progression; tumorigenic

Project Summary/Abstract: A major contributor to altered gene expression and chromatin reorganization in endocrine-related cancers is nuclear receptor signaling. Nuclear hormone receptors (NRs) are ligand-activated transcription factors that regulate diverse physiological functions including development, reproduction, homeostasis, and metabolism. They also represent an important group of prognostic indicators and therapeutic targets in hormone-driven cancers. In the F99 phase of this proposal, my focus is on studying the impact of dysregulation of the transcription factor TRβ, a member of the thyroid hormone receptor (TR) family in dedifferentiated thyroid tumors. The current prognosis for patients with resistant or recurrent thyroid cancer is extremely poor. Due to the lack of effective therapies, patients with advanced or metastatic thyroid cancer have a higher mortality rate than all other endocrine cancers combined. Importantly, restoration of TRβ function in malignant cells decreases tumor growth in xenograft studies. Despite a recognized role as a tumor suppressor, the mechanisms by which TRβ regulates tumor growth are not clear. Therefore, I will address the critical need for a deeper understanding of thyroid hormone receptor beta (TRβ) tumor suppressor mechanisms to inform the development more effective therapies for aggressive thyroid cancer. The directly regulated genes of TRβ will be defined through an integrated analysis of genome-wide binding and global gene expression data in thyroid cells. I will also determine the role that BRG1 plays in facilitating thyroid hormone induced chromatin remodeling, and its importance for maintenance of a normal transcriptional profile in thyroid cells. These data will provide us with key insights into thyroid cancer growth and progression, and allow for new target pathways to be explored as therapeutic options. In the K00 phase, I propose to pursue my broader interests in nuclear receptor mediated epigenetic programming and crosstalk in cancer in an environment which will allow me to expand my expertise hormone-mediated gene regulation and my technical skill set. I have identified a critical gap in our current understanding of the impact of hormone signaling on epigenetic regulatory mechanisms and changes in chromatin in structure. I plan to build upon my current training to develop a project that addresses the epigenetic mechanisms by which hormone signaling affects cancer cell identity, and translate these findings into clinically meaningful signatures. This work will add depth to our current understanding of nuclear receptor biology, and advance our ability to effectively treat hormone-dependent cancers with therapies that target nuclear receptors.

项目摘要/摘要： 内分泌相关癌症中基因表达和染色质重组改变的一个主要因素是 核受体信号传导。核激素受体 (NR) 是配体激活的转录因子， 调节多种生理功能，包括发育、繁殖、体内平衡和新陈代谢。 它们还代表了激素驱动的一组重要的预后指标和治疗目标。 癌症。 在这个提案的F99阶段，我的重点是研究转录因子失调的影响 TRβ，去分化甲状腺肿瘤中甲状腺激素受体（TR）家族的成员。目前的 耐药性或复发性甲状腺癌患者的预后极差。由于缺乏有效的 治疗方面，晚期或转移性甲状腺癌患者的死亡率高于所有其他癌症患者 合并内分泌癌。重要的是，恶性细胞中 TRβ 功能的恢复可减少肿瘤生长 在异种移植研究中。尽管TRβ作为肿瘤抑制因子的作用已得到公认，但其调节机制 肿瘤生长情况尚不清楚。因此，我将解决更深入了解甲状腺的迫切需要 激素受体β（TRβ）肿瘤抑制机制为开发更有效的疗法提供信息 用于侵袭性甲状腺癌。通过整合分析确定TRβ直接调控的基因 甲状腺细胞中的全基因组结合和全局基因表达数据。我还将确定BRG1的角色 促进甲状腺激素诱导的染色质重塑，及其对维持染色质的重要性 甲状腺细胞中的正常转录谱。这些数据将为我们提供有关甲状腺癌的重要见解 生长和进展，并允许探索新的靶标途径作为治疗选择。 在 K00 阶段，我建议追求对核受体介导的表观遗传编程更广泛的兴趣 和癌症中的串扰环境，这将使我能够扩展我的专业知识激素介导的基因 监管和我的技术技能。我发现我们目前对影响的理解存在严重差距 激素信号传导对表观遗传调控机制和染色质结构变化的影响。我计划建造 根据我目前的培训，开发一个项目来解决激素的表观遗传机制 信号传导会影响癌细胞的身份，并将这些发现转化为具有临床意义的特征。这部作品 将加深我们目前对核受体生物学的理解，并提高我们有效地 使用针对核受体的疗法治疗激素依赖性癌症。