Nuclear Receptor Regulation of Epigenetics in Endocrine-Related Cancers

项目概要/摘要： 内分泌相关癌症中基因表达改变和染色质重组的一个主要因素是 核受体信号核激素受体（NR）是配体激活的转录因子， 调节多种生理功能，包括发育、生殖、稳态和代谢。 它们也代表了一组重要的预后指标和治疗靶点， 癌的 在F99阶段，我的重点是研究转录因子调节异常的影响 TRβ是甲状腺激素受体（TR）家族的一员，在去分化甲状腺肿瘤中发挥作用。当前 具有抗性或复发性甲状腺癌的患者的预后极差。由于缺乏有效的 晚期或转移性甲状腺癌患者的死亡率高于所有其他治疗方法， 内分泌癌综合征重要的是，恶性细胞中TRβ功能的恢复降低了肿瘤生长 在异种移植研究中。尽管TRβ作为肿瘤抑制因子的作用是公认的，但它调节肿瘤的机制仍然不清楚。 肿瘤生长不明显。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，以告知开发更有效的治疗方法 治疗侵袭性甲状腺癌通过综合分析确定TRβ的直接调控基因 甲状腺细胞中全基因组结合和全球基因表达数据。我还将确定BRG 1 在促进甲状腺激素诱导的染色质重塑中发挥作用，以及其对维持甲状腺功能的重要性。 甲状腺细胞中正常的转录谱。这些数据将为我们提供甲状腺癌的关键见解 生长和进展，并允许探索新的靶向途径作为治疗选择。 在K 00阶段，我建议在核受体介导的表观遗传编程方面追求更广泛的兴趣 和癌症中的串扰，这将使我能够扩展我的专业知识， 法规和我的技术能力我已经确定了我们目前对影响的理解中的一个关键差距， 激素信号对表观遗传调节机制和染色质结构变化的影响。我计划建造 根据我目前的训练，我开发了一个项目，该项目旨在解决激素 信号传导影响癌细胞的身份，并将这些发现转化为临床上有意义的签名。这项工作 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 用靶向核受体的疗法来治疗依赖于细胞核的癌症。

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.