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Interrupting tumor progression by restoration of VDR expression

通过恢复 VDR 表达来阻断肿瘤进展

基本信息

批准号：
10435649
负责人：
Masako Nakanishi
金额：
$ 19.17万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10435649
关键词：
Accounting Affinity Age Apoptosis Back Binding Cell Adhesion Cell membrane Cells Cholecalciferol Colon Colonic Neoplasms Colonic Polyps Colorectal Cancer Conflict (Psychology)Cyclin D1 Cytometry DNA cassette Data Development Dose E-Cadherin Enterobacteria phage P1 Cre recombinase Excision Freezing Frequencies Gene Expression Gene Fusion Gene Targeting Generations Genes Human Immune Immunosuppression Impairment Incidence Interruption Intervention Trial Intestinal Neoplasms Intestinal Polyps Intestines Link Location LoxP-flanked allele Malignant Neoplasms Measures Mus Mutant Strains Mice Normal Cell Nuclear Outcome Oxidative Stress Pattern Pharmacology Preventive RXR Receptor Signaling Regulation Reporter Role Signal Pathway Signal Transduction Small Intestines System Tamoxifen Testing Time Tissues Transcriptional Activation Transgenes Tumor-infiltrating immune cells VDR gene Vitamin D Vitamin D supplementation Vitamin D2 Vitamin D3 Receptor WNT Signaling Pathway Work anti-tumor immune response anticancer activity base beta catenin c-myc Genes cell type chemokine colon tumorigenesis colorectal cancer prevention cytokine functional restoration genomic locus in vivo insight mouse model multiplexed imaging neoplastic cell novel novel therapeutic intervention promoter receptor receptor expression recruit response restoration spatiotemporal trafficking transcriptome tumor tumor growth tumor microenvironment tumor progression tumorigenesis

项目摘要

Project Summary Vitamin D has shown cancer preventive benefit in colorectal cancer (CRC). Despite some positive findings, conflicting data is also evident in human intervention trials that further study is warranted. An important observation linking the limited effects of vitamin D is a significant reduction in the levels of vitamin D receptor (VDR) activity. Our recent study in ApcΔ14/+ mice showed a loss of VDR expression in intestinal polyps, most likely accounting for the lack of cancer protection afforded by high-dose vitamin D3. Further analysis in this study and results of others suggested that compromised VDR expression may have influence on the regulation of β- catenin activation. Based on these observations, we hypothesize that forced re-expression of VDR within intestinal tumors can restore β-catenin control and potentially promote tumor regression in ApcΔ14/+ mice. To test this hypothesis, we will use our recently developed mouse model, Scd3iCreER/+, in which the expression of a floxed transgene can be driven specifically to intestinal tumors. To control VDR expression, we will utilize a floxed- stop system, in which Vdr expression is restricted by a STOP sequence until tamoxifen-controlled Cre recombinase is expressed. The successful creation of this conditional mouse model will allow us to directly test the influence of timed VDR expression on tumor regression in the intestine. In Aim 1, we plan to generate ROSA26LSL-Vdr-GFP mice, and then a compound mutant mice, ApcΔ14/+:ROSA26LSL-Vdr-GFP:Scd3iCreER/+. These mouse models will be thoroughly characterized to confirm the forced expression of VDR within intestinal tumors. In Aim 2, using the ApcΔ14/+:ROSA26LSL-Vdr-GFP:Scd3iCreER/+ mice, we will examine the impact of exogenous VDR reactivation on intestinal tumor development in a spatio-temporal manner. We will also profile the gene expression changes associated with the re-expression of VDR, focusing on the interplay between VDR and Wnt/β-catenin signaling pathways. Aim 3 will investigate the effect of exogenous expression of VDR on immune cell trafficking within the tumor microenvironment using cyTOF analysis. These proposed exploratory studies will provide a clear understanding of the anticancer activities of VDR, and ultimately enable us to uncover new therapeutic strategies for the reactivation of repressed VDR in CRC.

项目总结