Unraveling Racial Disparities in Portal Hypertension: A Clinical, Spectroscopic and SNP Approach

揭示门静脉高压症的种族差异：临床、光谱和 SNP 方法

• 批准号: 10321139
• 负责人: Vadim Backman
• 金额: $ 22.62万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-06 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321139
• 关键词: Unraveling; Racial; Disparities; Portal; Hypertension

Portal hypertension is the major consequence of cirrhosis which can lead to catastrophic complications such as massive, potentially exsanguinating hemorrhage from esophageal and gastric varices. Epidemiological studies indicate that African Americans (AAs) have higher mortality from portal hypertensive complications than Whites but the mechanism of disparity i.e. whether it is biologic or socio-economic remains unclear. Portal hypertension is characterized by increase in gut mucosal blood flow (gastropathy, colopathy) that in some studies has been shown to correlate with portal pressure and thus, severity of liver disease. We have developed a powerful spectroscopic technique- polarization gating spectroscopy (PGS) which can accurately measure gut mucosal blood flow. We have used PGS extensively to detect colorectal neoplasia by detecting increased blood flow in normal appearing colonic tissue but have not applied to issues in portal hypertension. Our colorectal data demonstrated distinct microvascular patterns in AAs and Whites. We have preliminary data with the more powerful next generation polarization gated spectroscopy (NG-PGS) that shows marked augmentation of duodenal microcirculation in cirrhosis. In addition, the biological basis of racial disparity is supported by racial differences in other circulatory disorders like systemic hypertension and in single nucleotide polymorphisms involved in genes involved in portal hypertension. The goal of this R21 is to elucidate the biological differences between AAs and Whites that lead to disparities in portal hypertension by utilizing a novel, less-intrusive spectroscopic microvascular duodenal mucosal biomarker that can be a potential surrogate for portal pressure. We will leverage the extraordinary resources at Boston University Medical Center, a safety net hospital serving a diverse population (40% AAs) with high number of liver visits. We will perform a prospective case control study, in with cirrhotics and stratify them by well-established clinical markers of clinically significant portal hypertension (CSPH) i.e. presence and size of varices and correlate it with race. We will examine if depth-selective NG-PGS assessment of duodenal microcirculation (total hemoglobin, oxygenation status and blood vessel radius) during standard of care diagnostic upper endoscopy for variceal detection will correlate with presence/size of varices and have distinct racial signatures in AAs and Whites (aim 1). We will then test the utility of the optimized duodenal microvasculature biomarker developed in aim 1, as a companion biomarker to detect changes in portal pressure by changes in duodenal microcirculation with a well-established therapeutic agent, octreotide test (aim 2). Using these novel and rigorous approaches, ours will the first study to provide into mechanisms of disparities in portal hypertension. Clinically, these studies will open new vistas in the management of portal hypertension. Future R01 applications may focus on NG-PGS as a companion biomarker to standard (β-blockers) or novel anti-portal hypertensive agent trial and as a potential point-of care test decoupled from endoscopy (direct insertion in stomach or rectal mucosa) to ameliorate access to care issues.

门脉高压是肝硬化的主要后果，可导致灾难性并发症，例如 流行病学研究显示食管和胃静脉曲张可能导致大量失血。 表明非裔美国人 (AA) 门脉高压并发症的死亡率高于白人 但差异的机制，即门脉高压是生物学的还是社会经济的，仍不清楚。 其特点是肠粘膜血流量增加（胃病、结肠病），在一些研究中已证实 研究表明，它与门静脉压力以及肝脏疾病的严重程度相关。 光谱技术——偏振门控光谱（PGS），可准确测量肠粘膜 我们使用 PGS 主要通过检测结直肠肿瘤中血流量的增加来检测结直肠肿瘤。 正常的结肠组织，但尚未应用于门脉高压问题。 我们已经掌握了更多的初步数据，证明了 AA 和白人的微血管模式不同。 强大的下一代偏振门控光谱 (NG-PGS) 显着增强了 此外，种族差异的生物学基础也得到了种族的支持。 其他循环系统疾病（如全身性高血压）和单核苷酸多态性的差异 该 R21 的目标是阐明生物学差异。 AA 和白人之间通过利用一种新颖的、侵入性较小的方法导致门静脉高压症的差异 光谱微血管十二指肠粘膜生物标志物可以作为门静脉压力的潜在替代品。 我们将利用波士顿大学医学中心的非凡资源，这是一家安全网医院，服务于 肝脏就诊次数较多的多样化人群（40% AA）我们将进行前瞻性病例对照研究， 与肝硬化相关，并通过临床上显着的门静脉高压的成熟临床标志物对它们进行分层 (CSPH)，即静脉曲张的存在和大小，并将其与种族相关联。我们将检查深度选择性 NG-PGS 是否存在。 评估十二指肠微循环（总血红蛋白、氧合状态和血管半径） 用于静脉曲张检测的诊断性上内窥镜检查标准将与静脉曲张的存在/大小相关 并且在 AA 和白人中具有独特的种族特征（目标 1），然后我们将测试优化的实用性。 目标 1 中开发的十二指肠微血管生物标志物，作为检测门静脉变化的伴随生物标志物 通过使用成熟的治疗剂奥曲肽试验改变十二指肠微循环来降低压力（目的 2). 使用这些新颖而严格的方法，我们将首次研究提供差异机制。 在临床上，这些研究将为门静脉高压的治疗开辟新的前景。 未来的 R01 应用可能侧重于 NG-PGS 作为标准（β-阻滞剂）或新型药物的伴随生物标志物 抗门静脉高压药物试验，并作为与内窥镜检查（直接 插入胃或直肠粘膜）以改善获得护理的问题。