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：
10591578
负责人：
Masako Nakanishi
金额：
$ 22.54万
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10591578
关键词：
Accounting Affinity Age Apoptosis Back Binding Cell Adhesion Cell membrane Cell physiology Cells Cholecalciferol Colon Colonic Adenoma Colonic Neoplasms Colonic Polyps Colorectal Cancer Cyclin D1 Cytometry Cytoplasm 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 Laboratories Link Location LoxP-flanked allele Malignant Neoplasms Measures Mus Mutant Strains Mice Normal Cell Nuclear Nuclear Translocation Outcome Oxidative Stress Pattern Preventive Proliferating RXR Receptor Signaling Regulation Reporter Repression Role Signal Pathway Signal Transduction Small Intestines System Tamoxifen Testing Time Tissues Transcriptional Activation Transgenes Tumor Promotion 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 beta catenin c-myc Genes cell type chemokine colon tumorigenesis colorectal cancer prevention cytokine functional restoration genomic locus in vivo inducible Cre insight mouse model multiplexed imaging neoplastic cell novel novel therapeutic intervention pharmacologic 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.

项目概要尽管有一些积极的发现，维生素 D 对结直肠癌 (CRC) 具有预防癌症的功效。在人类干预试验中，相互矛盾的数据也很明显，有必要进行进一步的研究。维生素 D 的有限作用与维生素 D 受体水平显着降低有关的观察结果我们最近对 ApcΔ14/+ 小鼠的研究表明，大多数肠息肉中 VDR 表达缺失。这可能是本研究中缺乏高剂量维生素 D3 提供的癌症保护作用的原因。和其他人的结果表明，受损的 VDR 表达可能会影响 β- 的调节基于这些观察，我们勇敢地面对 VDR 的强制重新表达。肠道肿瘤可以恢复 β-连环蛋白控制并可能促进 ApcΔ14/+ 小鼠的肿瘤消退。对于这个假设，我们将使用我们最近开发的小鼠模型 Scd3iCreER/+，其中 floxed 的表达为了控制 VDR 表达，我们将利用 floxed- 转基因。停止系统，其中 Vdr 表达受到 STOP 序列的限制，直到他莫昔芬控制的 Cre 该条件小鼠模型的成功创建将使我们能够直接进行测试。在目标 1 中，我们计划生成定时 VDR 表达对肠道肿瘤消退的影响。 ROSA26LSL-Vdr-GFP 小鼠，然后是复合突变小鼠，ApcΔ14/+:ROSA26LSL-Vdr-GFP:Scd3iCreER/+ 这些。将彻底表征小鼠模型，以确认 VDR 在肠道肿瘤内的强制表达。在目标 2 中，使用 ApcΔ14/+:ROSA26LSL-Vdr-GFP:Scd3iCreER/+ 小鼠，我们将检查外源性 VDR 的影响我们还将以时空方式重新激活肠道肿瘤的发展。与 VDR 重新表达相关的表达变化，重点关注 VDR 和 VDR 之间的相互作用目标 3 将研究 VDR 的外源表达对免疫的影响。这些拟议的探索性研究将使用 cyTOF 分析来研究肿瘤微环境中的细胞运输。让我们清楚地了解 VDR 的抗癌活性，并最终使我们能够发现新的 CRC 中重新激活受抑制的 VDR 的治疗策略。