Microvasculature in Colon Field Carcinogenesis: Clinical-Biological Implications

项目摘要 该项目的总体目标是开发一种直肠探头，用于最小侵入性高精度风险分层。 希望将其用于结肠癌筛查的精准医学方法，并有可能 化学预防(伴生生物标记物)。我们将采用尖端生物光子学(ISOCT)和生物 结合大规模人体研究阐明粘膜的临床/生物学意义的方法 早期增加血液供应(EIBS)。我们的多学科小组在两年内对EIBS进行了广泛的报道 通过发展尖端生物光子学技术进行动物模型和人体研究(n&gt；1000) 即偏振选通光谱(PGS)和最近的逆光谱光学相干性 断层扫描(ISOCT)。临床上，直肠EIBS对晚期腺瘤有很好的诊断能力(AUC&GT；0.8)，尽管 受到种族和性别的影响。从生物学上讲，我们关于早期结肠粘膜代谢的数据 在动物模型和人类中重新编程(类似Warburg效应)提供了一种潜在的机制 埃布斯。对于因果关系的洞察，试验性动物研究表明，通过 血管紧张素受体阻滞剂氯沙坦降低EIBS，同时抑制结肠肿瘤的发生。 此外，化学预防药物似乎逆转了癌前结肠的华宝样生理。 粘膜。我们假设EIBS是代谢重新编程的一种表现，可以用 ISOCT具有前所未有的精确度。在目标1(技术)中，我们将开发和验证ISOCT光纤 探讨并确定其在测定血红蛋白浓度、氧合状态和血管方面的准确性 不同浅层组织深度的直径。在目标2(生物标记物)中，我们将开发和验证直肠EIBS 晚期腺瘤的预测规则，其中预测规则针对性别和种族进行了优化 与血红蛋白氧合、深度、血管半径和密度相关的敏感生物标志物 &特异性≥为90%。对于代谢生理相关性，我们将询问短期初次结肠活检 细胞培养通过胞外通量分析(海马)作为华宝的生理标记物。我们将相互关联 通过ISOCT读数和肿瘤的存在(种族/性别特有)以及基因的表达 与华宝有牵连。在目标3(因果洞察力)中，我们将进行动物研究，以确定 使用氯沙坦(血管紧张素2抑制剂)和二甲双胍靶向EIBs和继发性代谢事件 (已知可以逆转Warburg效应的有希望的化学预防药物)将是一种潜在的腺瘤预防方法 策略。从生物学上讲，这项研究将明确证实eibs是新陈代谢的重要效应者。 重编程在结肠癌发生中的作用。临床上，直肠EIBS的侵入性最小，可能是 在初级保健环境中用于确定是否需要结肠镜检查以及滴定或停用 化学预防药物，以避免使没有获得治疗益处的患者接触到 这些药物的成本/毒性。这一新的范式可能预示着CRC预防的精准医学时代的到来。

Project Summary The overall goal of this project is to develop a rectal probe for minimally intrusive highly accurate risk stratification with the vision of utilizing it for a precision medicine approach to colon cancer screening and also potentially chemoprevention (companion biomarker). We will employ cutting edge biophotonics (ISOCT) and biological approaches combined with large scale human studies to elucidate the clinical/biological implications of mucosal early increase in blood supply (EIBS). Our multi-disciplinary group has extensively reported on EIBS in two animal models and human studies (n>1000) through the development of cutting-edge biophotonics technology namely the polarization gated spectroscopy (PGS) and more recently inverse spectroscopic optical coherence tomography (ISOCT). Clinically, rectal EIBS had excellent diagnostics of advanced adenomas (AUC >0.8) albeit impacted somewhat by race and gender. Biologically, our data on early colonic mucosal metabolic reprogramming (Warburg like effect) in both animal models and humans provides a potential mechanism for EIBS. For Causational Insights, pilot animal studies demonstrated that targeting microcirculation with the angiotensin receptor blocker losartan decreased EIBS with a concomitant suppression of colonic tumorigenesis. Furthermore, chemopreventive agents appear to reverse the Warburg-like physiology in the premalignant colonic mucosa. We hypothesize that EIBS is a manifestation of metabolic reprogramming that can be detectable with unprecedented accuracy with ISOCT. In aim 1 (technology), we will develop and validate the ISOCT fiberoptic probe and ascertain its accuracy for determining hemoglobin concentration, oxygenation status and blood vessel diameter at various superficial tissue depths. In aim 2 (biomarker), we will develop and validate a rectal EIBS prediction rule for the presence of advanced adenomas with prediction rule optimized for gender & race using biomarkers related to hemoglobin oxygenation, depth and blood vessel radius and density aiming for sensitivity & specificity ≥90%. For metabolic physiological correlates, we will interrogate the short term primary colon biopsy cell cultures via the extracellular flux analysis (Seahorse) as a physiological marker of Warburg. We will correlate with ISOCT readings and neoplasia presence (race/gender specific) along with the expressions of genes implicated in Warburg. In aim 3 (causational insight), we will perform animal studies to determine whether targeting the EIBS and secondary metabolic events using losartan (angiotensin 2 inhibitor) and metformin (promising chemopreventive agent known to reverse Warburg effects) would be a potential adenoma prevention strategy. Biologically, this study will provide definitive confirmation that EIBS is an important effector of metabolic reprogramming in colon carcinogenesis. Clinically, a rectal EIBS would be minimally intrusive and could be employed in the primary care setting to determine need for colonoscopy and also titrate or discontinue chemopreventive agents in order not to expose patients who do not derive a therapeutic benefit to the cost/toxicity of these agents. This new paradigm may herald the era of precision medicine in CRC prevention.