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原因，估计 美国32,000例死亡。应对疾病的目前措施不足，那里 是将临床前模型发现转化为患者的未满足的需求。但是，最近，一项研究对HCC建模 使用流体动力学的尾静脉注射的小鼠与睡美人的转座子系统（以下称为 “转座系统”）。在这里，发育的肿瘤通常与患者HCC相似69％ 突变体 - - - - - - 蛋白酶和酪氨酸激酶受体Met（B+M）。我发现包括iqgap1，一个脚手架 已知可以编排和促进致癌信号的蛋白质，加速B+M HCC的发展并导致原因 增强的肿瘤生长和严重程度。重要的是，我发现增加的IQGAP1表达促进了YAP1 信号传导并驱动NUAK2激酶的表达，NUAK2激酶是最近与HCC相关的可吸毒YAP1靶基因 肿瘤发生。这些发现表明，针对肝脏中的IQGAP1-YAP1网络是可能的 未来疗法的方向。我的目标是更好地了解IQGAP1如何调节分子机制 HCC，以及我的中心假设是IQGAP1将HCC的肿瘤发生及其工业驱动到 人源化的HCC系统将改善HCC疾病建模。我将以两个特定目的测试这一假设： AIM 1将建立HCC的人源化模型，并确定IQGAP1是否加剧了疾病病理。目的 2将通过靶向由由人源化的HCC模型验证的实用性。 IQGAP1过表达。 总体而言，该建议旨在解释IQGAP1在HCC生物学中的机械作用。 IQGAP1-YAP1 关系为HCC中的个性化医学提供了新的方向。此外，NUAK2升高 IQGAP1介导的YAP1活性引起的表达是我工作的一种机制。更好的 了解这种机制将为HCC中的激活的YAP1提供更大的见解。另外，我的 拟议的人源化HCC模型旨在加速临床前发现，并为潜在的潜力打开大门 个性化治疗方法使患者受益。我计划在我的独立 职业和匹兹堡大学为我提供了一个合适的环境 研究。 HCC是一个重大的公共卫生问题，我致力于研究这种疾病。和 我的合作者的全力支持，我相信我将能够完成拟议的研究。我的 提案以我当前的专业知识为基础，而K22机制提供的保护时间将使我 获得有关不可避免地支持我独立性的技术的经验。