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: 10394151
• 负责人: Noelle Elizabeth Gillis
• 金额: $ 8.61万
• 依托单位: UNIVERSITY OF MINNESOTA
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10394151
• 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 Profile; 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; Prognosis; 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; epigenetic silencing; genome-wide analysis; hormonal signals; hormone receptor-positive; hormone response element; hormone therapy; insight; interest; malignant endocrine gland neoplasm; member; mortality; novel; novel therapeutics; 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.

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