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提出一致的努力，以降低幽门螺杆菌（HP）复发的10-15％目前是患者经历的。调查人员在此计划项目中的先前工作赠款表明，放根疗法后，少数HP菌落持续在胃腺内。这些由于菌落居住在复发壁ches中，因此无法使用常规临床测试检测到菌落因此，对抗生素治疗具有抗性。高度敏感的分子技术可以揭示常规“阴性”胃组织学样本中HP的存在。项目3的中心假设是使用高度敏感的基于测序的技术来识别持续的HP生物并指导辐射既可以防止HP复发和阻止肿瘤进展。项目3的具体目的是：（1）利用胃皮细胞的基因表达谱作为胃肠道的预测指标 HP负个体中的化学（GIM）进展。（2）在HP组织学阴性受试者中发展分子风险分层策略。在AIM 1中，有300 hp负的受试者将进行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”表达式签名进入临床上有用的多重IHC测试。在AIM 2中，来自组织学阴性的GIM患者的样品对于活检的HP，将测序用于分子检测HP。一部分患者将参加随机，安慰剂对照试验评估抗生素治疗对分子HP滴度的影响。这个试验将证明基于测序的放射分配策略是否可以将HP燃烧降低到分子人类受试者中无法检测到的水平。