Targeting intracellular trafficking for cancer therapy

项目摘要/摘要 我的长期目标是在一家大型研究机构领导一个转化型癌症研究实验室。在我的整个 在博士前工作中，我培养了在多种情况下研究细胞内贩运的专业知识，包括 癌症代谢、磷酸酶信号转导和基于核苷酸的药物传递。我在这方面的总体目标 应用程序是完成我正在进行的研究，然后利用我研究内溶酶体的经验 在我的博士后工作期间，为了解决癌症免疫学中的关键悬而未决的问题而进行的贩运。对于F99 阶段，我将完成评估以细胞内转运为反义的小分子的研究 肿瘤和正常组织中的寡核苷酸(ASO)增强剂。ASO对核酸酶有16-20个碱基的抗性 寡核苷酸与靶RNA的碱基对，可引起其降解或改变其剪接。因此， ASO是终极平台技术，可以通过靶向来削弱致命的、耐药的肿瘤 “无法下药”的致癌基因。目前对肿瘤细胞的摄取不足限制了ASO在癌症中的临床应用 病人。通过将细胞生物学背景带入这个主要由生物化学家组成的领域，我获得了 确定了4种新的蛋白质，当靶向时，ASO活性史无前例地增加了100倍。对于K00 阶段，我将继续研究内溶酶体贩运，但将重点从ASO传递转移到抵抗 癌症免疫治疗的机制。拟议的培训计划背后的理由是，关键 将ASO运送到肿瘤细胞胞浆所需的运输步骤也被认为与抗 肿瘤免疫。结合我在细胞内贩运方面的专业知识和先进成像方面的技术技能 凭借在癌症免疫学实验室工作获得的深厚知识，很可能会取得重大进展 在这个领域。完成这些研究还将使我能够在这个竞争激烈的领域占据一席之地。 我可以在我自己的独立研究实验室中加以扩展。 该应用程序的总体培训目标是培养和培养管理、网络、 免疫学专业知识和写作技能，这是成功获得博士后奖学金和 一家主要研究机构的学术私家侦探。培训计划通过采取以下措施来实现这些培训目标 UCI及其充满活力、协作的癌症研究社区提供的关键资源的优势。

PROJECT SUMMARY/ABSTRACT My long-term goal is to lead a translational cancer research lab at a major research institution. Throughout my predoctoral work, I have cultivated expertise in studying intracellular trafficking in multiple contexts including cancer metabolism, phosphatase signaling, and nucleotide-based drug delivery. My overall objective in this application is to complete my ongoing studies and then leverage my experience studying endolysosomal trafficking to address critical open questions in cancer immunology during my postdoctoral work. For the F99 phase, I will complete studies evaluating small molecules that target intracellular trafficking as antisense oligonucleotide (ASO) potentiating agents in tumors and normal tissues. ASO are 16-20 bp nuclease-resistant oligonucleotides that base pair with a target RNA and can elicit its degradation or alter its splicing. Therefore, ASO are the ultimate platform technology that could cripple lethal, drug-resistant tumors by targeting “undruggable” oncogenes. Poor uptake into tumor cells currently limits the clinical use of ASO in cancer patients. By bringing a cell biology background to this field, which is populated primarily by biochemists, I have identified 4 novel proteins that when targeted increase ASO activity by an unprecedented 100-fold. For the K00 phase, I will continue to study endolysosomal trafficking, but shift my focus from ASO delivery to resistance mechanisms to cancer immunotherapies. The rationale underlying the proposed training plan is that the critical trafficking steps necessary to deliver ASO to the cytoplasm of tumor cells have also been implicated in anti- tumor immunity. Combining my expertise in intracellular trafficking and technical skills in advanced imaging with deep knowledge gained from working in a cancer immunology lab is likely to produce significant advances in this field. Completing these studies will also allow for me to develop a niche in this highly competitive field that I could expand upon in my own independent research lab. The overall training objective in this application is to develop and cultivate the management, networking, immunology expertise, and writing skills that are necessary to be successful in a postdoctoral fellowship and as an academic PI at a major research institution. The Training Plan addresses these training goals by taking advantage of critical resources provided by UCI and its vibrant, collaborative cancer research community.