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