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

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

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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.

项目摘要维生素D已显示出结直肠癌（CRC）的癌症预防益处。尽管有一些积极的发现，相互矛盾的数据也是人类干预试验中的证据，表明有必要进一步研究。一个重要的与维生素D的有限作用联系在一起的观察是维生素D受体水平的显着降低（VDR）活动。我们最近在APCΔ14/+小鼠的研究表明，肠息肉中VDR表达的丧失，大多数可能会考虑高剂量维生素D3提供的癌症保护。这项研究的进一步分析其他人的结果表明，VDR表达受损可能会影响β-的调节 Catenin激活。基于这些观察，我们假设强迫对VDR的强迫重新表达肠道肿瘤可以恢复β-catenin的控制，并可能促进APCΔ14/+小鼠的肿瘤消退。测试这个假设，我们将使用我们最近开发的鼠标模型SCD3ICREER/+，其中flox的表达转基因可以专门驱动到肠道肿瘤。为了控制VDR表达，我们将使用Floxed- 停止系统，其中VDR表达受到停止序列的限制，直到他莫昔芬控制的CRE 重组酶表示。该条件鼠标模型的成功创建将使我们能够直接测试定时VDR表达对肠道肿瘤回归的影响。在AIM 1中，我们计划生成 ROSA26LSL-VDR-GFP小鼠，然后是复合突变小鼠APCΔ14/+：ROSA26LSL-VDR-GFP：SCD3ICREER/+。这些小鼠模型将被彻底表征以确认肠道肿瘤中VDR的强制表达。在AIM 2中，使用APCΔ14/+：ROSA26LSL-VDR-GFP：SCD3ICREER/+小鼠，我们将检查外源VDR的影响以时空方式对肠道肿瘤发育的重新激活。我们还将介绍基因表达式变化与VDR的重新表达相关，重点是VDR和VDR之间的相互作用 Wnt/β-catenin信号通路。 AIM 3将研究VDR的外源表达对免疫的影响使用Cytof分析，肿瘤微环境内的细胞运输。这些拟议的探索性研究将对VDR的抗癌活动提供清晰的了解，并最终使我们能够发现新的 CRC中反射VDR的重新激活的治疗策略。