The gastrointestinal (GI) tract plays a key role in the processing of nutrients, absorption of pharmaceuticals and protection of the body from disease. Despite the importance of GI tract permeability to each of these processes, very little is understood about how mechanical motion of this organ (e.g. peristalsis) affects its permeability. Here we address this gap in our knowledge by systematically studying the influence of peristalsis on molecular and nanoparticle transport through the esophageal wall. Although our long-term goal is to understand permeability throughout the GI tract and its role in disease and disease interventions, our initial focus and the focus of this BRIGE application is on permeability of the esophagus because the esophagus is chronically understudied relative to other portions of the GI tract, yet relatively more accessible through esophagogastroduodenoscopy (EGD or endoscopy). We evaluate the hypothesis that peristalsis enhances permeability and that esophageal permeability is size dependent.
Intellectual Merit: This application is intellectually meritorious because it provides the first quantitative and mechanistic framework to evaluate the influence of pressure driven & stress driven pericellular perfusion (associated with peristalsis) on the transit of disease markers (e.g. the protein MBP-1), pharmaceutical agents, and nanoparticles of various sizes through the esophageal wall. The proposed systematic treatment couples experimental exploration with quantitative theory to provide comprehensive and quantitative insights into the biophysical mechanisms governing esophageal permeability. This work is critical to understanding the role of peristalsis in the etiology and pathogenesis of gastrointestinal diseases including eosinophilic esophagitis, a rapidly emerging orphan disease. The PI has full access to the resources of affiliated departments, the Health Sciences Core Facilities, and Center for Comparative Medicine.
Broader Impact: The proposed research program will have a variety of broad impacts. First, the proposed project will provide a quantitative infrastructure to design treatments to a variety of GI tract diseases ranging from esophageal diseases to autoimmune diseases including Crone?s diseases, where the esophageal lining is also compromised. The program will begin to elucidate the scientific principles necessary to understand the biological fate of environmental nanoparticles within the GI tract and the potential of nanoparticles as oral medicinal agents. The improved understanding of esophageal function will be broadly disseminated through high impact factor journal publications and public presentations. A key feature of the broadening participation plan is the inclusion of aspiring women and minority engineers, who will be invited to present their research at national meetings to reward their efforts, stimulate their excitement toward future research, and recognize their connectivity to other women and minorities in science. The graduate and undergraduates students funded through this proposal will be selected from underrepresented groups to broaden their participation. Women, Black, Hispanic, and Native American students will be specifically invited to apply for the positions this proposal creates. They will be asked to present their work in courses taught by the PI and to MESA clubs to provide direct role models for other underrepresented students. The proposed research will enhance the partnership between Chemical Engineering and the Schools of Medicine and Pharmacy. The proposed effort enlightens medicine by providing a better understanding of the function of normal and diseased esophageal models and enhances engineering by providing quantitative analysis of mass transport of biological
