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： 在内分泌相关癌症中，基因表达改变和染色质重组的主要因素是IS 核受体信号传导。 调节多样化的生理功能，包括发展，繁殖，稳态和代谢。 他们还抑制了一组重要的预测指标和激素驱动的治疗目标 癌症。 在提案的F99阶段，我的重点是研究转录因子失调的影响 TRβ，甲状腺激素受体（TR）家族的成员。 抗药性或复发癌症患者的预后极为差。 疗法，晚期或转移性甲状腺癌患者的死亡率率率高于所有其他 内分泌癌症合并。 在Xenograph研究中，尽管公认的作用是肿瘤的作用 肿瘤的生长尚不清楚。 激素受体β（TRβ）肿瘤抑制机制，以告知发育更有效的疗法 对于攻击性甲状腺癌 特性细胞中全基因组结合和全局基因表达数据的 促进甲状腺激素诱导染色质重塑的作用，而IST对于维持的重要性 这些数据中的正常转录特征将为我们提供甲状腺癌的关键 生长和发展，并允许将新的目标途径作为治疗选择探索。 在K00阶段，我提议追求对核受体介导的表观遗传程序的更广泛的兴趣 在防寒轮柳中的癌症中的crostalk我扩大了我的专业知识激素介导的基因 法规和我的技术技能。 表观遗传调节机制的激素信号和结构中的染色质变化。 在我目前的培训中，开发了一个针对激素的表观遗传机制的项目 信号会影响癌细胞的身份，并将发现转化为临床上有意义的签名 将为我们目前对核受体生物学的理解增加深度，并提高我们有效的能力 用靶向核受体的疗法治疗激素依赖性癌症。