Engineered Hydrogel Elucidates the Contribution of ECM Stiffness to Barrett's Esophagus Pathogenesis

工程水凝胶阐明了 ECM 硬度对巴雷特食管发病机制的影响

基本信息

批准号：
10664561
负责人：
Ricardo Cruz Acuña
金额：
$ 15.42万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2023-08-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10664561
关键词：
3-Dimensional Adenocarcinoma Adhesives Advisory Committees Affect Barrett Epithelium Barrett Esophagus Biochemical Biocompatible Materials Biologic Characteristic Biology Biomechanics Biomedical Engineering Cells Characteristics Clinic Cues Data Development Plans Disease Dysplasia Engineering Environment Epigenetic Process Epithelial Cells Esophageal Adenocarcinoma Esophageal Intraepithelial Neoplasia Esophagus Event Extracellular Matrix Faculty Fostering Foundations Funding Gene Expression Gene Expression Profile General Population Genes Growth High grade dysplasia Human Hyaluronic Acid Hydrogels In Vitro Individual Injury Institution Intestinal Metaplasia MDM2 gene Medical center Mentored Research Scientist Development Award Mentorship Metaplasia Modeling Morphology Mutation Organoids Pathogenesis Pathway interactions Patients Peptides Persons Pharmaceutical Preparations Population Pre-Clinical Model Prevention Proliferating Property Research Research Personnel Research Proposals Risk Role Signal Transduction Squamous Epithelium System TP53 gene Testing Time Tissues Training United States National Institutes of Health Universities Work Xenograft procedure base editing career development clinically significant collaborative environment defined contribution density effectiveness testing genomic aberrations human disease human model in vivo in vivo evaluation induced pluripotent stem cell inhibitor innovation intestinal epithelium novel novel therapeutics permissiveness pre-doctoral response small molecule inhibitor stem cell derived tissues stem cell model targeted treatment tenure track therapeutic target translational medicine translational therapeutics treatment response

项目摘要

Project Summary Barrett’s esophagus (BE) is a disease in which the squamous epithelium of the esophagus is replaced by a columnar intestinal epithelium (termed metaplasia), and is believed to affect 3-4 million people in the US. BE patients have a 30-125-fold greater risk of developing esophageal adenocarcinoma (EAC) via intermediate low- grade and high-grade dysplastic states, when compared to the general population. The pathogenesis of BE involves epigenetic/genomic aberrations (e.g. TP53 mutations), and an interplay with microenvironmental cues. Recent studies have demonstrated that ECM stiffening is associated with metaplasia (or BE)-dysplasia- adenocarcinoma sequence, and my novel data reveal that increased ECM stiffness, a critical biomechanical property, is characteristic of BE pathogenesis. This underscores a compelling need to understand mechanisms that foster BE metaplasia and dysplasia in the context of ECM stiffness. Therefore, this proposal will integrate my unique predoctoral training in biomaterial engineering with my new proposed career development training in epithelial cell and organoid biology to utilize an engineered HA-based hydrogel to elucidate the contribution of ECM stiffness in BE pathogenesis, and to identify matrix-activated therapeutic targets. This bioengineering approach will be combined with TP53 mutation (in the epithelium of BE) to understand BE pathogenesis. The overarching hypothesis of my proposal is that ECM stiffness modulation can recapitulate a dysplastic BE state, revealing novel underlying mechanisms of the disease. I will pursue this hypothesis through the following interrelated Specific Aims: Aim 1 focuses on establish a hydrogel platform to study the pro-dysplastic contribution of matrix properties in patient-derived BE organoids. Aim 2 focuses on in vitro identification and in vivo evaluation of therapeutic targets in stiff matrix-exposed patient-derived BE organoids. Aim 3 focuses on utilizing an hiPSC-derived platform of BE to elucidate the cooperation between intrinsic and extrinsic factors contributing to BE pathogenesis. This work is innovative because it uses an advanced bioengineering approach to elucidate the functional roles of ECM stiffness in human BE pathogenesis. Successful completion of this proposal will be both scientifically and clinically significant by defining the contribution of biomechanics to BE and laying a foundation for novel therapies to disrupt matrix stiffness in BE. The research proposal, training/career development/mentorship plans, advisory committee, RCR training, protected time for research, and institutional support will provide the foundation for me to transition to an eventual independent NIH funded tenure-track faculty investigator, who blends principles of basic biology, bioengineering, and translational medicine.

项目概要巴雷特食管 (BE) 是一种食管鳞状上皮被鳞状上皮取代的疾病。柱状肠上皮（称为化生），据信影响美国 3-400 万人。中低水平患者发生食管腺癌 (EAC) 的风险增加 30-125 倍与一般人群相比，BE 的发病机制。涉及表观遗传/基因组畸变（例如 TP53 突变）以及与微环境线索的相互作用。最近的研究表明，ECM 硬化与化生（或 BE）-发育不良- 腺癌序列，我的新数据揭示了 ECM 硬度的增加，这是一个关键的生物力学性质，是 BE 发病机制的特征，这强调了了解机制的迫切需要。在 ECM 僵硬的情况下促进 BE 化生和发育不良因此，该提案将整合。我在生物材料工程方面独特的博士前培训以及我新提出的职业发展培训上皮细胞和类器官生物学利用基于 HA 的工程水凝胶来阐明 ECM 僵化在 BE 发病机制中的作用，并确定基质激活的治疗靶点。该方法将结合TP53突变（在BE的上皮细胞中）来了解BE的发病机制。我的提议的总体假设是 ECM 刚度调制可以重现发育不良的 BE 状态，我将通过以下内容来揭示该疾病的新的潜在机制。相互关联的具体目标：目标 1 侧重于建立一个水凝胶平台来研究促发育不良基质特性对患者来源的 BE 类器官的贡献目标 2 侧重于体外鉴定和体内鉴定。目标 3 的重点是对暴露于硬基质的患者来源的 BE 类器官中的治疗靶点进行体内评估。利用 hiPSC 衍生的 BE 平台阐明内在因素和外在因素之间的合作这项工作具有创新性，因为它采用了先进的生物工程方法。阐明 ECM 僵硬在人类 BE 发病机制中的功能作用。通过定义生物力学对 BE 的贡献，该提案将具有科学和临床意义并为破坏 BE 基质硬度的新疗法奠定基础。培训/职业发展/指导计划、咨询委员会、RCR 培训、受保护的研究时间、机构支持将为我过渡到最终独立的 NIH 资助提供基础终身教授研究员，融合了基础生物学、生物工程和转化原理药品。