Inflammatory Bowel Diseases
Presentation at the November 19, 2007 NCDD Meeting
Chair: Daniel K. Podolsky, MD
Vice Chair: Eugene B. Chang, MD
Research Goal 1
Establish objective basis for clinical diagnosis, detailed phenotype, and disease activity.
Research Goal 1
Objectives
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Develop a comprehensive genotypic profile.
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Define informative immunophenotypic profiles.
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Develop methodology and value for a microbiomic profile.
Research Goal 1
Objectives (continued)
Research Goal 2
Develop an individualized approach to risk evaluation and management based on genetic susceptibility.
Research Goal 2
Objectives
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Complete identification of risk susceptibility genes among diverse patient populations.
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Determine the functional role of IBD associated gene variants in pathophysiologic pathways leading to IBD.
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Determine impact of environmental factors on disease associated genetic variants.
Research Goal 2
Objectives (continued)
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Define genetic subset/phenotype-genotype correlations.
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Identify and assess relevant pharmacogenetic variations.
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Correlate genotype (disease susceptibility and pharmacogenetic) with response to therapy and incorporate genotypes into clinical trials.
Research Goal 2
Objectives (continued)
Research Goal 3
Modulate the intestinal microbiome (IM) to prevent or control IBD.
Research Goal 3
Objectives
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Achieve a comprehensive molecular and functional delineation of the IM in all relevant niches across different individuals/populations.
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Understand the factors that regulate the composition and functional characteristics of the IM including host factors (environmental, genetic, and mucosal function).
Research Goal 3
Objectives (continued)
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Characterize the IM associated with IBD by location and disease activity.
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Develop experimental tools for understanding IM complexity and clinical methods for characterization and monitoring of the IM in patients.
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Develop experimental in vivo systems for pre-clinical studies of IM therapeutic modulation.
Research Goal 4
Effectively modulate the mucosal immune system to prevent or ameliorate IBD.
Research Goal 4
Objectives
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Define all relevant immune cell populations by their functional characteristics and differentiation pathways.
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Define the factors regulating innate and adaptive immunity, both genetic and environmental.
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Delineate innate and adaptive immune interaction with the microbiome.
Research Goal 4
Objectives (continued)
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Identify relevant inflammatory mediators in effecting IBD injury and symptomatic manifestations of IBD and mechanisms regulating inflammatory processes.
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Characterize alterations in innate and adaptive immune function in IBD (including regulatory cell populations) especially related to microbiome.
Research Goal 5
Sustain the health of the mucosal surface.
Research Goal 5
Objectives
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Understand the functional biology of the epithelial compartment and identify alterations in IBD.
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Identify and characterize the stem cell compartment and develop the capacity to modulate lineage specification and maturation.
Research Goal 5
Objectives (continued)
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Understand the structural and functional elements of the mucosal barrier (including the role of luminal flora and nutrients) and alterations associated with IBD.
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Define the systems biology of the intestinal mucosa including interactions among epithelial and lamina propria cell populations as well as integration with enteric nervous, endocrine and vascular elements.
Research Goal 6
Promote regeneration and repair of injury in IBD.
Research Goal 6
Objectives
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Understand normal reparative processes and characterize their alteration in IBD.
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Define the impact of the microbiome on tissue repair.
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Develop strategies to modulate repair processes to restore functional capacity.
Research Goal 6
Objectives (continued)
Research Goal 7
Provide effective tools for clinical evaluation and intervention.
Research Goal 7
Objectives
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Develop and validate technologies to evaluate disease status including biomarkers and non-invasive as well as novel endoscopic imaging methods.
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Develop innovative endoscopic and more physiologic surgical interventions.
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Develop effective and non-toxic mechanism-based pharmacologic therapies including manipulation of the microbiome.
Research Goal 7
Objectives (continued)
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Develop tools for more efficient clinical development of investigational agents, including surrogate markers of response.
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Identify tools to more effectively identify pre-malignant mucosa and interventions to reduce cancer risk.
Research Goal 8
Ameliorate or prevent adverse effects of IBD on growth and development in children and adolescents.
Research Goal 8
Objectives
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Develop interventions that promote normal social interactions and mental health in all patients.
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Define the mechanisms that produce growth delay.
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Identify approaches that enable normal growth and development.
Major Challenges/Steps To Achieve Goals
Major Challenges/Steps To Achieve Goals
Basic Mechanisms of IBD
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National and international collaborations for sample acquisition, analysis of genetic loci across diverse populations, and research on well-characterized patients followed on a longitudinal basis to define genotype-phenotype correlation
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Rapid, quantitative, high-throughput techniques to define individual members of complex microbial communities, robust bioinformatic tools, and metagenomic datasets with comprehensive data on provenance and host phenotype
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New computational tools, such as in silico techniques for modeling microbial populations and microbial-host interactions
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An intestinal microbiome project beginning with commissioning computational tools and pilot projects
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Techniques to isolate and sustain primary epithelial cell populations in vitro for research on these critical cells populations and their functional alteration in IBD.
Major Challenges/Steps To Achieve Goals
Translational Research
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Robust in vitro model systems (including primary cell and organ cultures) which recapitulate the complexity of intestinal mucosa and can be experimentally manipulated
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Better integration of basic and clinical research efforts for more effective translational progress
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Animal models with validated clinical relevance in which response to intervention is predictive of response in man
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Consortia of investigators across institutions to expedite research to understand the functional implications of gene variants associated with IBD
Clinical Research and Discovery
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Objective and consistent criteria for diagnosis and substratification of patients
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Overcome barriers to therapeutic trials in pediatric populations
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Standards for clinical trials including end-points,incorporation of surrogate endpoints, phenotyping and DNA collection
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Strategies for enrolling patients in clinical trials
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Larger cadre of clinical investigators and clinical trial infrastructure to support an expanded national and international program of interventional clinical trials for IBD
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Greater public awareness and understanding of IBD through public educational programs
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Clinical summit of investigators, all stake holding agencies, and industry
Page last updated: January 07, 2008