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.

肝细胞癌是癌症相关死亡的第五大常见原因，据估计 美国每年有3.2万人死亡。目前抗击这种疾病的措施不足，而且存在 是一种未得到满足的需求，将临床前模型的研究结果转化为患者。然而，最近的一项研究将肝癌模拟为 使用睡美人转座子系统(以下简称为 “转座系统”)。在这里，发生肿瘤的基因与患者肝细胞癌有69%的相似之处 突变的ꞵ-连环蛋白和酪氨酸激酶受体MET(B+M)。我发现包括IQGAP1在内的一个脚手架 已知的协调和促进致癌信号的蛋白质，加速B+M肝癌的发展和原因 增强了肿瘤的生长和严重程度。重要的是，我发现IQGAP1表达增加会促进YAP1 信号转导并驱动最近与肝细胞癌相关的YAP1靶基因NUAK2的表达 致癌作用。这些发现表明，在肝脏中靶向IQGAP1-YAP1网络可能是一种可能的 未来治疗的方向。我的目标是更好地理解IQGAP1是如何调节 我的中心假设是IQGAP1推动了肝癌的发生，并将其整合到一个 人性化的肝细胞癌系统将改进肝细胞癌疾病的建模。我将在两个具体目标上检验这一假设： 目的1建立人源化的肝细胞癌模型，并确定IQGAP1是否加重了疾病的病理。目标 2将通过靶向由以下驱动的致癌河马信号来验证人源化肝癌模型的实用性 IQGAP1过度表达。 总之，这项提议旨在解释IQGAP1的S在肝癌生物学中的机制作用。IQGAP1-YAP1 关系为肝癌的个体化用药提供了新的方向。此外，提升的NUAK2 IQGAP1介导的YAP1活性导致的表达对我的工作来说是一个新的机制。更好 了解这一机制将为深入了解Hcs中激活的YAP1提供更多的信息。此外，我的 提出的人源化肝细胞癌模型旨在加速临床前的发现并打开潜在的大门 个性化的治疗方法，使患者受益。我计划在我独立后继续这项工作 职业生涯和匹兹堡大学为我提供了一个合适的环境来实现我的设计 学习。肝细胞癌是一个重大的公共卫生问题，我致力于研究这种疾病的职业。使用 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 提案建立在我目前的专业知识基础上，K22机制提供的保护时间将使我 以获得技术方面的经验，这些技术将不可避免地支持我的独立性。