UNFOLDED PROTEIN RESPONSE IN DRUG SENSITIVITY AND RESISTANCE

药物敏感性和耐药性中未折叠的蛋白质反应

• 批准号: 7668518
• 负责人: Linda M Hendershot
• 金额: $ 29.99万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7668518
• 关键词: Affect; Aftercare; Angiogenesis Inhibitors; Angiogenic Factor; Animal Model; Animals; Antineoplastic Agents; Apoptotic; Buffers; Carmustine; Cell Cycle Arrest; Cell physiology; Cells; Characteristics; Cisplatin; Class; Collaborations; Coupled; Cultured Cells; DNA Damage; Data; Doctor of Philosophy; Drug resistance; Elements; Embryo; Engineering; Fibroblasts; Funding; Gene Targeting; Genetic Transcription; Human; Knock-out; Malignant Childhood Neoplasm; Mediating; Molecular Chaperones; Mus; Numbers; Pathway interactions; Pediatric Neoplasm; Personal Satisfaction; Pharmaceutical Preparations; Play; Poison; Process; Proteins; Range; Regulatory Element; Research Personnel; Resistance; Role; Sampling; Stress; Testing; Tissue Array Analysis; Topoisomerase II; Topotecan; Toxic effect; Transcription Process; Transcriptional Activation; Type I DNA Topoisomerases; Up-Regulation; Upper arm; Vascular Endothelial Growth Factors; Vascular blood supply; Vascular remodeling; Vascularization; Xenograft Model; Xenograft procedure; antitumor agent; cell killing; chemotherapeutic agent; clinically relevant; drug efficacy; drug sensitivity; experience; genetic analysis; human TOP1 protein; molecular pathology; neoplastic cell; programs; promoter; protein folding; research study; response; temozolomide; tumor; tumor growth

Due to inadequate blood supply, tumor cells exist in a compromised microenvironment that impinges on normal protein folding and can activate the unfolded protein response (DPR). In addition to contributing to tumor growth and survival, data from cell culture studies demonstrate that pharmacological activation of the UPR can also alter the sensitivity of cells to chemotherapeutic agents, making them more sensitive in some cases and more resistant in others. In the previous cycle of funding, we showed that UPR activation is both necessary and sufficient to reduce the sensitivity to topoisomerase II targeted therapy and found that this is a result of PERK activation. We propose genetic analyses in the coming cycle to identify the responsible target(s) and determine to what extent the UPR affects drug sensitivity in xenograft studies. Conversely, UPR activation increases the sensitivity of cells to cisplatin, which damages both DMA and proteins. As a number of anti-cancer agents have similar characteristics, we propose to explore interactions between these agents and the UPR and to determine the mechanism or interaction where synergies exist. Given the broad affects of the UPR on cellular processes, it is likely that this pathway will interact with other chemotherapeutic agents. Indeed, our preliminary data demonstrate that activation of the UPR reduces the sensitivity of cells to the topoisomerase I poison, topotecan. Finally, anti-angiogenic agents are being used to inhibit tumor vascularization, which should contribute to UPR activation in the tumor. However, recent data demonstrate that they can also promoter vascular remodeling, making it unclear how this will affect UPR activation. Since the UPR leads to both increased transcription and processing of pro-angiogenic factors, it is essential to understand the affect of anti-angiogenic agents on the UPR and to determine if the UPR plays a role in resistance to these agents. In this proposal, we describe experiments to determine the mechanisms by which the UPR increases sensitivity to some agents while decreasing sensitivity to others, explore possible interactions with additional chemotherapeutic agents, and determine the affect of UPR activation on drug sensitivity in animal models. In addition, we will extend our initial examination of UPR activation in tumor samples to other UPR targets and multiple types of tumors to establish the scope of the significance of our findings to pediatric cancers.

由于血液供应不足，肿瘤细胞存在于受损的微环境中， 正常蛋白质折叠，并可激活未折叠蛋白质反应（DPR）。除了有助于 肿瘤生长和存活，来自细胞培养研究的数据表明， UPR还可以改变细胞对化疗剂的敏感性，使它们在某些情况下更敏感。 在其他病例中，耐药性更强。在上一轮融资中，我们表明，普遍定期审议的激活既 必要和足够的，以减少敏感性拓扑异构酶II靶向治疗，并发现这是一个 PERK激活的结果。我们建议在下一个周期进行基因分析，以确定 靶点，并确定UPR在异种移植研究中影响药物敏感性的程度。相反地， UPR激活增加了细胞对顺铂的敏感性，顺铂会破坏DMA和蛋白质。作为 许多抗癌药物具有相似的特征，我们建议探索这些药物之间的相互作用。 （c）确定各机构和普遍定期审议的作用，并确定存在协同作用的机制或相互作用。鉴于广泛的 由于UPR对细胞过程的影响，这一途径可能会与其他途径相互作用， 化疗剂。事实上，我们的初步数据表明，普遍定期审议的激活减少了 细胞对拓扑异构酶I毒物拓扑替康的敏感性。最后，正在使用抗血管生成剂 抑制肿瘤血管形成，这应该有助于肿瘤中UPR的激活。但最近的 数据表明，它们也可以促进血管重塑，但尚不清楚这将如何影响 普遍定期审议启动。由于UPR导致促血管生成因子的转录和加工增加， 因此，了解抗血管生成剂对UPR的影响并确定其是否与UPR相关是至关重要的。 UPR在对这些药剂的抗性中起作用。在这个建议中，我们描述了实验，以确定 普遍定期审议增加对某些药物的敏感性而降低对其他药物的敏感性的机制， 探索与其他化疗药物的可能相互作用，并确定UPR的影响 在动物模型中对药物敏感性的激活。此外，我们将延长对普遍定期审议的初步审查， 在肿瘤样品中激活其他UPR靶点和多种类型的肿瘤，以建立 我们的发现对儿科癌症的意义。