Cause and Effect Relationships Between Glycation and the Ancestry Specific Tumor Stroma

糖化与祖先特异性肿瘤基质之间的因果关系

基本信息

批准号：
10586185
负责人：
David Paul Turner
金额：
$ 48.11万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586185
关键词：
Acceleration Adenocarcinoma Advanced Glycosylation End Products African American African ancestry Age Aging Allografting Basic Science Binding Biological Biological Availability Black race Cancer Burden Cancer Patient Cells Chemicals Chronic Circulation Clinical Coculture Techniques Cohort Studies Collagen Communities Consumption Data Demographic Factors Deposition Development Diet Dimerization Disease Disease Progression Down-Regulation ECM receptor Education Elements Energy consumption Environment Environmental Risk Factor Epidemiology Epithelial Cells Epithelium Ethnic Origin Exposure to Extracellular Matrix Fibroblasts Food Chain Foundations Future Genes Growth Human Immune Incidence Individual Ingestion Intake Integrins Intervention Invaded Laminin Louisiana MMP9 gene Malignant Neoplasms Malignant neoplasm of prostate Manuscripts Matrix Metalloproteinases Mediating Membrane Metabolic Metabolism Microfluidics Modeling Molecular Mus North Carolina Not Hispanic or Latino Obesity Oncogenic Organ Outcome Participant Pathway interactions Patients Peptide Hydrolases Peptides Play Population Populations at Risk Preventive Process Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Prostatic Intraepithelial Neoplasias Prostatic Neoplasms RNA Splicing Race Regulation Research Resources Risk Factors Role Serum Signal Transduction Socioeconomic Factors Source Spliced Genes TNF gene Testing Therapeutic Tissues Treatment Protocols Tumor Biology Variant Visualization Vulnerable Populations Work Xenograft Model biochip cancer cell cancer health disparity cell growth cohort dietary epidemiology study fruits and vegetables functional decline genetic regulatory protein genome analysis glycation health disparity health inequalities high risk in vitro Model in vivo innovation men migration molecular site mortality novel outcome disparities pharmacologic programs prostate cancer cell line prostate cancer risk receptor for advanced glycation endproducts reconstitution research study sugar transcriptome sequencing treatment strategy tumor tumor growth tumor progression tumorigenic wasting whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Whole genome analyses support the tumor stroma as the main site of molecular change that promotes deadly prostate cancer in African American men. However, complimentary basic research studies showing a direct cause-and-effect relationship are lacking. As our bodies use the sugars, we consume for energy they generate waste chemicals known as metabolites. One such group of metabolites is known as advanced glycation end products or AGEs for short. AGE accumulation in our tissues and organs causes their functional decline and accelerates the aging process. AGEs represent intrinsic biological elements within health disparity risk factors that align with the stromal profiles that influence prostate cancer in African American men. This group has previously shown that AGEs are elevated in the circulation and tumors of prostate cancer patients with highest levels being observed in men with African ancestry and in more aggressive tumors. Using diet as a surrogate for health inequity, a key and novel finding from this research is that dietary consumption of AGEs can directly accelerate prostate tumor growth. Dietary-AGE mediated effects on tumor growth were shown to be dependent upon stromal signaling by the transmembrane receptor for AGE (RAGE). AGE-RAGE signaling was associated with an activated stroma similar to that observed in African American men with prostate cancer. This was defined by the increased presence of cancer associated fibroblasts (CAFs) and the downregulation of matrix associated genes. The long-term, objective is to integrate ancestral tumor biology into the multilevel framework of health inequity constructs to inform on cancer disparity outcomes. The study hypothesis is that “increased AGE bioavailability contributes to rapid tumor progression in AA men with PCa cancer”. The study will use a combination of prostate cancer cell lines and unique mouse tumor models to define a direct cause-and-effect relationship between AGEs and ancestry specific crosstalk in the tumor associated stroma. It will also assess if the consumption of AGEs has a positive correlation with prostate cancer risk using data from large human cohort studies. By establishing the mechanistic consequences AGEs found in the food chain on ancestry specific tumor biology, defined strategies to limit their accumulation in at risk populations, such as African American men with prostate cancer, may be viewed as cancer preventive or therapeutic strategies when combined with existing treatment regimens.

项目摘要/摘要整个基因组分析支持肿瘤基质作为分子变化的主要部位在非裔美国人中促进致命的前列腺癌。但是，免费基本研究表明缺乏直接因果关系。当我们的身体使用糖时，我们消耗的能量会产生已知的废物化学物质作为代谢产物。这样的一组代谢产物被称为高级糖基化终产物或年龄很短。我们组织和器官中的年龄积累会导致其功能下降，并且加速衰老过程。年龄代表健康差异内的内在生物学元素与影响非裔美国人前列腺癌的基质特征相符的危险因素男人。该组先前已经表明，年龄在循环和肿瘤中升高在非洲血统和更具侵略性的肿瘤。利用饮食作为健康不平等的替代物，是一种关键和新颖的发现这项研究是，饮食消费量可以直接加速前列腺肿瘤的生长。饮食年龄介导的对肿瘤生长的影响依赖于基质跨膜受体的信号传导年龄（RAGE）。年龄段信号是相关的活化的基质类似于在前列腺癌的非洲裔美国男性中观察到的基质。这是由癌症相关成纤维细胞（CAF）和基质相关基因的下调。长期的目的是将祖传肿瘤生物学整合到多层次框架中健康不平等构造以告知癌症差异结果。研究假设是 “增加的生物利用度有助于AA患有PCA的男性的快速肿瘤进展癌症”。该研究将结合前列腺癌细胞系和独特的小鼠肿瘤定义年龄与祖先之间直接因果关系的模型肿瘤中的串扰。它还将评估年龄的消费是否具有使用大型人类队列研究的数据，与前列腺癌风险正相关。通过建立食物链中的机械后果年龄特定的肿瘤生物学，定义了限制其在风险种群中积累的策略，例如患有前列腺癌的非裔美国人可能被视为癌症预防或治疗策略与现有治疗方案结合使用。