权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Frizzled 9 loss and regulation in preventing the progression of pre-malignant lung lesions

卷曲 9 的丢失和调节在预防癌前肺部病变进展中的作用

基本信息

批准号：
10153456
负责人：
Meredith A Tennis
金额：
$ 37.23万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-09 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153456
关键词：
Animal Model Binding Biological Markers Biometry Biopsy Cancer Etiology Cancer Model Cancer Prevention Trial Cancer cell line Carcinogens Cell Line Cells Cessation of life Chemoprevention Clinical Clinical Chemoprevention Clinical Data Clinical Research Clinical Treatment Clinical Trials Data Differentiation Antigens Discipline Dysplasia Epithelial Epithelial Cells Excision Future Genetic Transcription Growth Human Iloprost In Situ Hybridization In Vitro Intelligence Knock-out Knockout Mice Lesion Lung Maintenance Malignant neoplasm of lung Measures MicroRNAs Modeling Molecular Mus Non-Small-Cell Lung Carcinoma Oral Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Phase Physicians Play Positioning Attribute Prevention Prevention Research Prevention approach Prevention strategy Prevention trial Preventive Prostaglandins I Pulmonary Pathology RNA Regulation Role Scientist Signal Transduction Smoker Squamous cell carcinoma Testing Therapeutic Tissues Transgenic Mice Translational Research Tumor Burden United States analog base biomarker identification bronchial epithelium cell growth cellular targeting cigarette smoke data modeling effective intervention epithelial to mesenchymal transition exposure to cigarette smoke follow-up former smoker human subject improved in silico in vitro activity in vivo in vivo Model individualized prevention knock-down lung cancer prevention mRNA Expression mouse model overexpression pre-clinical predicting response predictive marker predictive modeling premalignant prevent receptor response response biomarker screening success therapeutic target transcription factor treatment response trial design tumor

项目摘要

Project Summary Lung cancer continues to be the leading cause of cancer death in the United States. Limited therapeutic success means that prevention strategies may be the most effective intervention for reducing the burden of lung cancer. In a phase II prevention trial, treatment with the oral prostacyclin analogue iloprost resulted in normalization of endobronchial dysplasia (a precursor to squamous carcinoma) in former smokers. About half of former smokers, but not current smokers, had improved endobronchial dysplasia in response to iloprost, suggesting the potential for targeted prevention in specific subjects. Iloprost requires the transmembrane receptor Frizzled 9 (Fzd9), not the prostacyclin receptor (IP), for its preventive activity in vitro. Fzd9 expression is decreased by cigarette smoke and increased by prostacyclin. Restoring Fzd9 expression in NSCLC cell lines inhibits transformed growth, suggesting that Fzd9 has a role in lung epithelium maintenance. Despite its importance in the lung and for iloprost activity, we do not understand Fzd9 regulation or how it interacts with iloprost. In Aim 1, we will induce Fzd9 expression loss in normal lung in vitro and in vivo. We hypothesize that loss of Fzd9 expression leads to abnormal growth in lung epithelial cells and is required for prostacyclin reduced tumor burden in vivo. In Aim 2, we will identify pathways that regulate Fzd9 expression and downstream signaling activity. We hypothesize that Fzd9 expression is controlled by transcription factors and miRNA identified in preliminary screening studies. We also hypothesize, based on preliminary data and in silico modeling, that iloprost directly binds Fzd9 to activate critical prevention signaling. In Aim 3, we will test Fzd9 as a predictive biomarker for response to iloprost. We expect that Fzd9 expression in baseline endobronchial biopsies from the iloprost clinical trial will predict response to iloprost treatment. Overall, these studies will define the role of Fzd9 in the mechanism of iloprost prevention and elucidate regulation of Fzd9. Identification of markers predicting a favorable response to prostacyclin will facilitate personalized prevention to maximize treatment benefit and allow for more intelligent trial design. Our proposal promotes the vital but less common approach to translational research, where clinical data is shared with basic scientists in an effort to understand the mechanisms behind clinical observations and improve future clinical studies. Interdisciplinary teams are key to our translational research. We have scientists and physicians with expertise in molecular and cellular studies, medicinal chemistry, animal models of lung cancer, clinical chemoprevention trials, lung pathology, and biostatistics. This project will have a broad impact as a model for prevention and translational research across disciplines.

项目摘要肺癌仍然是美国癌症死亡的首要原因。有限治疗成功意味着预防策略可能是减轻艾滋病负担的最有效干预措施肺癌。在II期预防试验中，口服前列环素类似物伊洛前列素治疗导致曾经吸烟者的支气管腔内发育不良(鳞癌的先兆)的正常化。大约一半既往吸烟者，而不是现在吸烟者，对伊洛前列素的反应改善了支气管内发育不良，这表明有可能在特定对象中进行有针对性的预防。伊洛前列素需要跨膜受体Frizzled9(Fzd9)，而不是前列环素受体(IP)，因为其体外预防活性。FZD9表达式因吸烟而减少，因前列环素而增加。恢复非小细胞肺癌细胞中Fzd9的表达 LINES抑制转化生长，提示Fzd9在肺上皮细胞维持中起作用。尽管它的对于肺和伊洛前列腺素活性的重要性，我们不了解Fzd9的调节或它如何与伊洛前列素。在目标1中，我们将在体外和体内诱导正常肺组织中Fzd9的表达缺失。我们假设 Fzd9表达缺失导致肺上皮细胞异常生长，是前列环素所必需的减轻体内肿瘤负担。在目标2中，我们将确定调节Fzd9表达和下行信令活动。我们假设Fzd9的表达受转录因子和在初步筛选研究中确定了miRNA。我们还假设，基于初步数据和在计算机模拟，iloprost直接与Fzd9结合，激活关键的预防信号。在目标3中，我们将测试 FZD9作为预测伊洛前列素疗效的生物标志物。我们预计Fzd9在基线中的表达来自伊洛前列素临床试验的支气管镜活检将预测伊洛前列素治疗的反应。总的来说，这些研究将确定Fzd9在预防伊洛前列腺素的机制中的作用，并阐明Fzd9的调控。识别对前列环素有良好反应的标志物将有助于个性化预防以最大限度地提高治疗效益，并允许进行更智能的试验设计。我们的提案促进了至关重要的不太常见的转化性研究方法，在这种方法中，临床数据与基础科学家共享了解临床观察背后的机制，并改进未来的临床研究。跨学科团队是我们翻译研究的关键。我们有具有专业知识的科学家和医生分子和细胞研究、药物化学、肺癌动物模型、临床化学预防试验、肺病理学和生物统计学。该项目将产生广泛的影响，作为预防和预防的典范跨学科的翻译研究。