HITI/Helmsley Trust Pilot Grants in Crohn's Disease

Suggested Research Areas

Applications are invited that address the five areas indicated below:

1. Devising a novel in vitro intestinal epithelial cell culture system that will facilitate evaluation of mechanisms of Crohn’s disease
   • Engineered 3-dimensional constructs that faithfully capture the structure and function of the intestinal epithelium can bridge the gap between mouse models and clinical disease and are compatible with a high throughput strategy for assessment of pathophysiologic mechanisms and efficacy of drug candidates
   • Architecturally robust approaches incorporating other intestinal cell types, including cells of the immune system, that enable in vitro study of cellular-microbial interactions
2. Developing real-time readout systems that can interrogate the dynamics of microbiome, epithelial and immune cell interactions
   • Creation of "reporter" constructs - bacteria, nanoparticles or nanocontainers - that can sense and record changes in key properties of, and interactions between, the microbiome and epithelial or immune cells
   • Engineered constructs that preferentially colonize specific geographies of the gut, thereby providing highly informative real-time evaluation of gut physiology
   • Advanced imaging technologies - either alone, or in concert with an engineered sensor - or use of miRNA or small molecule libraries to interrogate functional relevance/causality of aberrant biomarkers or functions in models of Crohn’s disease
3. Generating a creative and integrative analysis of the intestinal microbiome that moves beyond cataloging the luminal milieu
   • Proof of concept in mice, or use of human organ-donor tissue, to define clinical approaches for undisturbed and geographically diverse sampling of the microbiome at the epithelial surface, the mucous layer and the lumen
   • Mouse studies that characterize these geographically restricted microbial populations to determine their diversity, longevity and biological impact on mammalian cell function
   • A systems biology approach to characterize complex interactions among the microbiome, the intestinal epithelium, and the associated immunological compartment
   • Other novel approaches for deconstructing the complexity of the microbiome and providing unique perspectives on the symbiotic relationships between microbiota and intestinal cells
4. Formulating studies directed at the dynamic balance between injury and repair in the intestinal epithelium
   • The role of cell metabolism - and its perturbation by endogenous or environmental inducers of cellular stress response pathways - both in epithelial cell injury and the subsequent repair process
   • Investigation of other critical homeostatic functions - implicated or not by GWAS - which, if perturbed, increase the risk of inflammation and loss of epithelial barrier function
   • The relationship between inflammation and predisposition to colorectal cancer, as it impacts Crohn’s patients directly, and as a means to better define the transition events between normal and neoplastic growth
5. Devising approaches to patient stratification that recognize the marked variability in their pathophysiology, genetics, and response to therapy
   • Evaluation of early onset disease patients; integration of protective allele studies into GWAS of disease susceptibility; and identification and analysis of contributions of rare genetic variants to disease susceptibility
   • More effective linkage of GWAS to mechanism, histology, patient disease status and response to therapeutics