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， 美国每年有32，000人死亡。目前防治艾滋病的措施不足， 是一个未满足的需求，将临床前模型的发现转化为患者。然而，最近，一项研究模拟了 小鼠使用流体动力学尾静脉注射睡美人转座子系统（下文称为 “转座子系统”）。在这里，发展的肿瘤与患者HCC的遗传相似性为69%， 突变体β-连环蛋白和酪氨酸激酶受体MET（B+M）。我发现，包括IQGAP 1，一个支架， 已知协调和促进致癌信号的蛋白质，加速B+M HCC的发展并导致 增强肿瘤生长和严重性。重要的是，我发现IQGAP 1表达的增加促进了YAP 1 信号传导并驱动NUAK 2激酶的表达，NUAK 2激酶是最近与HCC相关的可药用YAP 1靶基因 肿瘤发生这些发现表明，靶向肝脏中的IQGAP 1-YAP 1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IQGAP 1如何调节细胞凋亡的分子机制。 我的中心假设是IQGAP 1驱动HCC肿瘤发生，并将其整合到一个细胞中。 人源化HCC系统将改善HCC疾病建模。我将在两个具体目标中测试这个假设： 目的1建立人源化HCC模型，并确定IQGAP 1是否加重疾病病理。目的 2将通过靶向致癌Hippo信号传导来验证人源化HCC模型的实用性，所述致癌Hippo信号传导由 IQGAP 1过表达。 总的来说，该提案旨在解释IQGAP 1在HCC生物学中的机制作用。IQGAP 1-YAP 1 这种关系为HCC的个体化治疗提供了新的方向。此外，NUAK 2升高 由IQGAP 1介导的YAP 1活性导致的表达是我的工作的新机制。更好 理解这一机制将为肝癌中激活的YAP 1提供更深入的了解。另外我 提出的人源化HCC模型旨在加速临床前发现，并为潜在的 个性化的治疗方法，使患者受益。我计划在我独立期间继续这项工作。 匹兹堡大学为我提供了一个合适的环境来实现我的设计 问题研究HCC是一个重要的公共卫生问题，我致力于研究这种疾病的职业生涯。与 在我的合作者的全力支持下，我相信我将能够完成拟议的研究。我 我的建议基于我目前的专业知识，K22机制提供的受保护时间将使我能够 来获得技术上的经验，这将不可避免地支持我的独立性。