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Immune-regulating MHC class I-like proteins and colorectal cancer risk

免疫调节 MHC I 类蛋白与结直肠癌风险

基本信息

批准号：
10116347
负责人：
Anna Prizment
金额：
$ 7.12万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116347
关键词：
Accounting Age American Cancer Society Atherosclerosis Risk in Communities Binding Biological Blood Blood Circulation Body mass index CD8B1 gene Cancer Etiology Cell surface Cells Cessation of life Cleaved cell Clinical Colorectal Cancer Colorectal Neoplasms Communities Data Data Analyses Demographic Factors Development Diagnosis Diagnostic Dose Early Diagnosis Freezing Funding Genes Genotype Goals Immune Immune response Immune system Immunologic Markers Immunologic Surveillance Immunotherapy Incidence Individual Ligands MICA protein Major Histocompatibility Complex Malignant Neoplasms Measures Mendelian randomization Methods Mica Microsatellite Repeats Mutation Natural Killer Cells Participant Pathway interactions Plasma Play Population Study Prospective Studies Protein Inhibition Protein Secretion Proteins Public Health Race Reporting Risk Risk Factors Role Sampling Smoking Stage at Diagnosis Testing Time Transmembrane Domain Tumor-infiltrating immune cells Variant Visit Woman atherosclerosis risk base biracial cancer type clinical biomarkers cohort colon cancer patients colorectal cancer prevention colorectal cancer progression colorectal cancer risk colorectal cancer screening cost efficient follow-up gastrointestinal gastrointestinal epithelium genetic variant genome sequencing genome wide association study high risk lifestyle factors men mortality neoplastic cell novel novel strategies overexpression prospective sex tumor whole genome

项目摘要

PROJECT SUMMARY Immune biomarkers may be useful for early detection and prevention of colorectal cancer. However, very little is known about the potent immune pathway involving major histocompatibility complex (MHC) class I-like proteins in colorectal cancer. These proteins, expressed by gastrointestinal cells, serve as major ligands for natural killer cells. However, they may be cleaved from the cell surface and released into blood in a soluble form – the mechanism widely used by tumors to escape from immune surveillance even at early stages of colorectal cancer development. In addition, MHC class I-like genes are highly polymorphic with functional mutations changing the secretion of these proteins into bloodstream and altering the binding between tumor and immune cells. These biological pathways provide opportunities for blood-based colorectal cancer screening and development of immune therapies aimed at the neutralization of MHC class I-like proteins in blood, although the utility of these proteins as clinical biomarkers in colorectal cancer remain to be determined. Our main hypothesis is that MHC class I-like proteins contribute to the risk of colorectal cancer development. To test this novel hypothesis, we propose to conduct a secondary data analysis in a prospective population- based study – Atherosclerosis Risk in the Community cohort using existing information on six plasma MHC class I-like proteins measured three times over 20 years of follow-up, genotyping data in MHC class I-like genes and data about CRC and its risk factors. The use of existing data will allow for quick and cost efficient testing of our hypothesis. Understanding the role of MHC class I-like proteins in colorectal cancer is clinically important because inhibition of these proteins in blood would provide a novel opportunity for controlling colorectal tumor development and early detection. 1

项目摘要免疫生物标志物可能有助于结直肠癌的早期检测和预防。然而，已知涉及主要组织相容性复合体（MHC）I类抗原的有效免疫途径。结直肠癌中的蛋白质。这些蛋白质由胃肠道细胞表达，作为主要的配体，自然杀伤细胞然而，它们可以从细胞表面裂解，并以可溶性微球形式释放到血液中。形式-肿瘤广泛使用的机制，即使在早期阶段也能逃避免疫监视。结直肠癌的发展。此外，MHC I类基因具有高度多态性，突变改变了这些蛋白质分泌到血液中，并改变了肿瘤细胞之间的结合，和免疫细胞。这些生物学途径为血液来源的结直肠癌提供了机会筛选和开发免疫疗法，旨在中和MHC-I类蛋白，血液，尽管这些蛋白质作为结肠直肠癌临床生物标志物的效用仍有待确定。我们的主要假设是，MHC I类蛋白有助于结直肠癌的发展风险。为了检验这一新的假设，我们建议在前瞻性人群中进行二次数据分析- 基于研究-使用六种血浆MHC的现有信息的社区队列中的动脉粥样硬化风险在20年的随访中测量了三次I类蛋白，MHC I类基因分型数据关于CRC及其危险因素的基因和数据。使用现有数据将允许快速和具有成本效益测试我们的假设。了解MHC I类蛋白在结直肠癌中的作用重要的是，因为抑制血液中的这些蛋白质将为控制结直肠肿瘤的发展和早期发现。 1