Investigating IQGAP1, a scaffold protein, in liver biology and Hepatocellular Carcinoma to overcome barriers in in vivo models

研究肝脏生物学和肝细胞癌中的支架蛋白 IQGAP1，以克服体内模型中的障碍

• 批准号: 10370768
• 负责人: Evan R Delgado
• 金额: $ 17.98万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-20 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370768
• 关键词: Acceleration; Animal Model; Automobile Driving; BAY 54-9085; Binding; Biological; Biological Assay; Biology; Cancer Etiology; Cell Proliferation; Cells; Cessation of life; Chemicals; Complex; Data; Development; Disease; Disease Management; Disease model; Engineering; Environment; Fluorescence Resonance Energy Transfer; Future; Genes; Genetic; Genomics; Goals; Growth; Hepatocyte; Human; Human Genetics; Image; Injections; Lentivirus; Link; Liver; Luciferases; Measures; Mediating; Methods; Modeling; Molecular; Mus; Mutation; Nuclear; Nuclear Translocation; Oncogenes; Oncogenic; Organ Donor; Organ Transplantation; Pathology; Patients; Pattern; Phosphotransferases; Pre-Clinical Model; Preclinical Drug Development; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Public Health; Quantitative Reverse Transcriptase PCR; Receptor Protein-Tyrosine Kinases; Reporter; Reproducibility; Research; Research Design; Research Personnel; Resources; Role; Scaffolding Protein; Severities; Signal Transduction; Sleeping Beauty; Study models; System; Tail; Techniques; Testing; Therapeutic; Time; Translating; Translations; Transplantation; Tumor Burden; United States; Universities; Veins; Viral; Western Blotting; Work; Xenograft procedure; beta catenin; career; combat; experience; genetic signature; human disease; humanized mouse; improved; in vitro activity; in vivo Model; inhibitor; innovation; insight; lentivirally transduced; liver cancer model; mutant; novel; overexpression; patient derived xenograft model; personalized medicine; personalized therapeutic; phase I trial; pre-clinical; promoter; small hairpin RNA; targeted treatment; therapeutic development; tool; transcriptome sequencing; transcriptomics; tumor; tumor growth; tumorigenesis

Hepatocellular Carcinoma (HCC) is the 5th most common cause of cancer-related death with an estimated 32,000 annual deaths in the United States. Current measures to combat the disease are insufficient and there is an unmet need translating pre-clinical model findings to patients. Recently, though, a study modeled HCC in mice using hydrodynamic tail vein injections with the Sleeping Beauty transposon system (referred hereafter as the “transposon system”). Here, tumors that develop are 69% genetically similar to patient HCCs driven by mutant ꞵ-catenin and the tyrosine kinase receptor MET (B+M). I found that including IQGAP1, a scaffold protein known to orchestrate and promote oncogenic signals, accelerates B+M HCC development and causes enhanced tumor growth and severity. Importantly, I found increasing IQGAP1 expression promotes YAP1 signaling and drives the expression of NUAK2 kinase, a druggable YAP1 target gene recently linked to HCC oncogenesis. These findings indicate that targeting the IQGAP1-YAP1 network in the liver could be a possible direction for future therapies. I aim to better understand how IQGAP1 regulates the molecular mechanisms in HCC, and my central hypothesis is that IQGAP1 drives HCC oncogenesis and its incorporation into a humanized HCC system will improve HCC disease modeling. I will test this hypothesis in 2 specific aims: Aim 1 will establish a humanized model of HCC and determine if IQGAP1 exacerbates disease pathology. Aim 2 will validate the utility of the humanized HCC model by targeting oncogenic Hippo signaling driven by IQGAP1 overexpression. Overall, this proposal aims to explain IQGAP1’s mechanistic role in HCC biology. The IQGAP1-YAP1 relationship provides a novel direction for personalized medicine in HCC. In addition, elevated NUAK2 expression resulting from IQGAP1 mediated YAP1 activity is a mechanism novel to my work. Better understanding this mechanism will provide greater insight to activated YAP1 in HCCs. In addition, my proposed humanized HCC model is intended to accelerate pre-clinical findings and open the door to potential personalized therapeutic approaches to benefit patients. I plan to pursue this work during my independent career and the University of Pittsburgh provides a suitable environment for me to carry out my designed studies. HCC is a significant public health concern and I am committed to a career studying the disease. With full support from my collaborators, I am confident that I will be able to complete the proposed research. My proposal builds on my current expertise and the protected time provided by the K22 mechanism will enable me to gain experience in techniques that will inevitably support my independence.

肝细胞癌 (HCC) 是癌症相关死亡的第五大常见原因，据估计 美国每年有 32,000 人死亡。目前对抗该疾病的措施还不够充分 将临床前模型结果转化为患者的需求尚未得到满足。不过，最近一项研究模拟了 HCC 小鼠使用水动力尾静脉注射睡美人转座子系统（以下简称 “转座子系统”）。在这里，所形成的肿瘤与由以下因素驱动的患者 HCC 具有 69% 的遗传相似性： 突变体 ꞵ-catenin 和酪氨酸激酶受体 MET (B+M)。我发现包括IQGAP1，一个脚手架 已知可协调和促进致癌信号、加速 B+M HCC 发展和原因的蛋白质 增强肿瘤生长和严重程度。重要的是，我发现增加 IQGAP1 表达会促进 YAP1 信号传导并驱动 NUAK2 激酶的表达，NUAK2 激酶是最近与 HCC 相关的可药物 YAP1 靶基因 肿瘤发生。这些发现表明，靶向肝脏中的 IQGAP1-YAP1 网络可能是一种可能的方法。 未来治疗的方向。我的目标是更好地了解 IQGAP1 如何调节分子机制 HCC，我的中心假设是 IQGAP1 驱动 HCC 肿瘤发生并将其纳入 人性化 HCC 系统将改善 HCC 疾病模型。我将通过两个具体目标来检验这个假设： 目标 1 将建立 HCC 人源化模型并确定 IQGAP1 是否会加剧疾病病理。目的 2 将通过靶向由以下因素驱动的致癌 Hippo 信号来验证人源化 HCC 模型的实用性 IQGAP1 过度表达。 总的来说，该提案旨在解释 IQGAP1 在 HCC 生物学中的机制作用。 IQGAP1-YAP1 这种关系为 HCC 个性化医疗提供了新的方向。此外，NUAK2 升高 IQGAP1 介导的 YAP1 活性产生的表达对于我的工作来说是一种新颖的机制。更好的 了解这一机制将为 HCC 中激活的 YAP1 提供更深入的了解。另外，我的 提出的人性化 HCC 模型旨在加速临床前发现并打开潜在的大门 个性化治疗方法使患者受益。我计划在独立期间从事这项工作 匹兹堡大学为我提供了一个合适的环境来实现我的职业生涯 研究。 HCC 是一个重大的公共卫生问题，我致力于研究该疾病。和 在我的合作者的全力支持下，我有信心能够完成拟议的研究。我的 该提案建立在我目前的专业知识之上，K22 机制提供的受保护时间将使我能够 获得技术经验，这将不可避免地支持我的独立性。