Project 3: Molecular Risk Stratification of Gastric Precancerous Lesions

项目3：胃癌前病变分子风险分层

基本信息

批准号：
10715764
负责人：
JOO HA HWANG
金额：
$ 38.95万
依托单位：
STANFORD 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：
2023-09-20 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10715764
关键词：
16S ribosomal RNA sequencing Antibiotic Resistance Antibiotic Therapy Antibiotics Back Biological Assay Biological Specimen Banks Biology Biopsy Blinded Carcinoma Chile Chromosome Mapping Clinical Clinical Management Cohort Studies DNA Sequence Alteration Detection Development Diagnosis Dysplasia Endoscopy Enrollment Epithelial Cells Epithelium Evaluation Gastric Adenocarcinoma Gastric Glands Gastric Tissue Gene Expression Gene Expression Profile Genetic Genomics Gland Goals Helicobacter Infections Helicobacter pylori Histologic Histology Histopathology Immunohistochemistry Individual Intervention Label Lesion Link Machine Learning Malignant Neoplasms Methods Molecular Mucous Membrane Network-based Organism Outcome Pathologist Patients Pattern Placebos Precancerous Conditions Prevalence Prognostic Marker Program Research Project Grants Randomized Recrudescences Research Research Personnel Risk Risk Factors Risk Reduction Sampling Severities Slide Specimen Stains Stomach Surrogate Endpoint Techniques Technology Testing Training Translating Universities Work adjudication antimicrobial arm biomarker panel cancer risk cell type clinical data repository cohort design experience expression vector gastric intestinal metaplasia gastrointestinal high risk histological specimens human subject improved malignant stomach neoplasm neural network novel patient subsets premalignant prevent progression risk randomized placebo controlled trial recruit risk stratification transcriptome sequencing tumor tumor progression

项目摘要

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.

摘要 – 项目 3 项目3提出共同努力将幽门螺杆菌（Hp）复发率降低10-15% 患者目前所经历的情况结果表明，根除治疗后，少数 Hp 菌落仍存留在胃腺深处。使用传统的临床测试可能无法检测到菌落，因为菌落位于复发生态位中因此对抗生素治疗具有抗药性。高度敏感的分子技术可以揭示这一点。传统“阴性”胃组织学样本中存在 Hp 项目 3 的中心假设是：使用高度灵敏、基于测序的技术来识别持久性 Hp 微生物并指导根除可以预防 Hp 复发并阻止肿瘤进展项目 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道的预测因子 Hp 阴性个体的化生 (GIM) 进展。 (2) 制定 HP 组织学阴性受试者的分子风险分层策略。在目标 1 中，300 名 Hp 阴性受试者将接受 RNA 测序，并与“高风险”模式保持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”表达特征。目标 2 中，来自组织学阴性的 GIM 患者的样本。将对活检中的 Hp 进行测序，以进行 Hp 分子检测。随机、安慰剂对照试验评估抗生素治疗对 Hp 分子滴度的影响。将证明基于测序的根除策略是否可以从分子水平上减少 HP 负担人类受试者中检测不到的水平。