Project 3: Molecular Risk Stratification of Gastric Precancerous Lesions

摘要-项目3 项目3提出了一个共同努力，以减少10-15%的幽门螺杆菌（Hp）复发率 目前患者所经历的。该计划项目资助中的研究人员之前的工作已经 表明根除治疗后，少量Hp菌落在胃腺深处持续存在。这些 使用常规临床试验可能无法检测到菌落，因为菌落位于复发壁龛中 因此对抗生素治疗有抵抗力。高灵敏度的分子技术可以揭示 在常规的“阴性”胃组织学样本中存在Hp。项目3的核心假设是， 使用高度敏感的测序技术来识别持久性Hp微生物并指导根除 既可预防Hp复发，又可阻止肿瘤进展。项目3的具体目标是： (1)利用胃上皮细胞的基因表达谱作为胃肠疾病的预测因子 在Hp阴性个体中的化生（GIM）进展。 (2)在Hp组织学阴性受试者中制定分子风险分层策略。 在目标1中，300名Hp阴性受试者将接受RNA测序，并与“高风险”模式一致 将通过基因表达载体进行评估。然后我们将翻译'高风险'的表达签名 临床上有用的多重免疫组化检测在目标2中，来自组织学阴性的GIM患者的样本 将对活检标本上的Hp进行测序，以进行Hp的分子检测。一部分患者将参加 随机、安慰剂对照试验，评价抗生素治疗对分子Hp滴度的影响。本试验 将证明基于测序的根除策略是否可以将Hp负担降低到分子水平， 在人类受试者中检测不到的水平。

ABSTRACT – PROJECT 3 Project 3 proposes a concerted effort to decrease the 10-15% rate of Helicobacter pylori (Hp) recrudescence that is currently experienced by patients. Previous work by the investigators in this Program Project Grant has shown that a small number of Hp colonies persist deep within the gastric glands after eradication therapy. These colonies may not be detected using conventional clinical tests, as the colonies reside in recrudescence niches that are consequently resistant to antibiotic treatment. Highly sensitive molecular technology can reveal the presence of Hp in conventionally ‘negative’ gastric histology samples. The central hypothesis of Project 3 is that use of highly sensitive, sequencing-based technology to identify persistent Hp organisms and guide eradication may both prevent Hp recrudescence and arrest neoplastic progression. The specific aims of Project 3 are: (1) Leverage gene expression profiles of gastric epithelial cells as a predictor of gastric intestinal metaplasia (GIM) progression in Hp negative individuals. (2) Develop molecular risk-stratification strategies in Hp histology negative subjects. In Aim 1, 300 Hp negative subjects will undergo RNA sequencing, and concordance with the ‘high-risk’ patterns will be assessed through a gene expression vector. We will then translate the ‘high-risk’ expression signature into a clinically useful multiplex IHC test. In Aim 2, samples from patients with GIM who are histology negative for Hp on biopsies will be sequenced for molecular detection of Hp. A subset of patients will participate in a randomized, placebo-controlled trial evaluating the effect of antibiotic therapy on molecular Hp titers. This trial will demonstrate whether a sequencing-based eradication strategy can reduce Hp burden to molecularly undetectable levels in human subjects.