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Inflammatory Bowel Diseases

Presentation at the November 19, 2007 NCDD Meeting

Chair: Daniel K. Podolsky, MD

Vice Chair: Eugene B. Chang, MD

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Research Goal 1

Establish objective basis for clinical diagnosis, detailed phenotype, and disease activity.

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Research Goal 1
Objectives

• Develop a comprehensive genotypic profile.

• Define informative immunophenotypic profiles.

• Develop methodology and value for a microbiomic profile.

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Research Goal 1
Objectives (continued)

• Develop technology for effective anatomic and functional imaging of disease location and activity.

• Establish useful correlative and predictive biomarkers.

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Research Goal 2

Develop an individualized approach to risk evaluation and management based on genetic susceptibility.

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Research Goal 2
Objectives

• Complete identification of risk susceptibility genes among diverse patient populations.

• Determine the functional role of IBD associated gene variants in pathophysiologic pathways leading to IBD.

• Determine impact of environmental factors on disease associated genetic variants.

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Research Goal 2
Objectives (continued)

• Define genetic subset/phenotype-genotype correlations.

• Identify and assess relevant pharmacogenetic variations.

• Correlate genotype (disease susceptibility and pharmacogenetic) with response to therapy and incorporate genotypes into clinical trials.

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Research Goal 2
Objectives (continued)

• Use genotypic variations to define disease risk and to predict natural history and response to therapy.

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Research Goal 3

Modulate the intestinal microbiome (IM) to prevent or control IBD.

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Research Goal 3
Objectives

• Achieve a comprehensive molecular and functional delineation of the IM in all relevant niches across different individuals/populations.

• Understand the factors that regulate the composition and functional characteristics of the IM including host factors (environmental, genetic, and mucosal function).

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Research Goal 3
Objectives (continued)

• Characterize the IM associated with IBD by location and disease activity.

• Develop experimental tools for understanding IM complexity and clinical methods for characterization and monitoring of the IM in patients.

• Develop experimental in vivo systems for pre-clinical studies of IM therapeutic modulation.

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Research Goal 4

Effectively modulate the mucosal immune system to prevent or ameliorate IBD.

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Research Goal 4
Objectives

• Define all relevant immune cell populations by their functional characteristics and differentiation pathways.

• Define the factors regulating innate and adaptive immunity, both genetic and environmental.

• Delineate innate and adaptive immune interaction with the microbiome.

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Research Goal 4
Objectives (continued)

• Identify relevant inflammatory mediators in effecting IBD injury and symptomatic manifestations of IBD and mechanisms regulating inflammatory processes.

• Characterize alterations in innate and adaptive immune function in IBD (including regulatory cell populations) especially related to microbiome.

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Research Goal 5

Sustain the health of the mucosal surface.

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Research Goal 5
Objectives

• Understand the functional biology of the epithelial compartment and identify alterations in IBD.

• Identify and characterize the stem cell compartment and develop the capacity to modulate lineage specification and maturation.

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Research Goal 5
Objectives (continued)

• Understand the structural and functional elements of the mucosal barrier (including the role of luminal flora and nutrients) and alterations associated with IBD.

• 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.

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Research Goal 6

Promote regeneration and repair of injury in IBD.

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Research Goal 6
Objectives

• Understand normal reparative processes and characterize their alteration in IBD.

• Define the impact of the microbiome on tissue repair.

• Develop strategies to modulate repair processes to restore functional capacity.

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Research Goal 6
Objectives (continued)

• Identify mechanisms to reverse or remodel fibrotic response.

• Identify interventions that improve care of patients with surgically modified gut.

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Research Goal 7

Provide effective tools for clinical evaluation and intervention.

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Research Goal 7
Objectives

• Develop and validate technologies to evaluate disease status including biomarkers and non-invasive as well as novel endoscopic imaging methods.

• Develop innovative endoscopic and more physiologic surgical interventions.

• Develop effective and non-toxic mechanism-based pharmacologic therapies including manipulation of the microbiome.

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Research Goal 7
Objectives (continued)

• Develop tools for more efficient clinical development of investigational agents, including surrogate markers of response.

• Identify tools to more effectively identify pre-malignant mucosa and interventions to reduce cancer risk.

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Research Goal 8

Ameliorate or prevent adverse effects of IBD on growth and development in children and adolescents.

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Research Goal 8
Objectives

• Develop interventions that promote normal social interactions and mental health in all patients.

• Define the mechanisms that produce growth delay.

• Identify approaches that enable normal growth and development.

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Major Challenges/Steps To Achieve Goals

• Basic mechanisms of IBD

• Translational research

• Clinical research and discovery

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Major Challenges/Steps To Achieve Goals

Basic Mechanisms of IBD

• 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

• 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

• New computational tools, such as in silico techniques for modeling microbial populations and microbial-host interactions

• An intestinal microbiome project beginning with commissioning computational tools and pilot projects

• Techniques to isolate and sustain primary epithelial cell populations in vitro for research on these critical cells populations and their functional alteration in IBD.

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Major Challenges/Steps To Achieve Goals

Translational Research

• Robust in vitro model systems (including primary cell and organ cultures) which recapitulate the complexity of intestinal mucosa and can be experimentally manipulated

• Better integration of basic and clinical research efforts for more effective translational progress

• Animal models with validated clinical relevance in which response to intervention is predictive of response in man

• Consortia of investigators across institutions to expedite research to understand the functional implications of gene variants associated with IBD

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Clinical Research and Discovery

• Objective and consistent criteria for diagnosis and substratification of patients

• Overcome barriers to therapeutic trials in pediatric populations

• Standards for clinical trials including end-points,incorporation of surrogate endpoints, phenotyping and DNA collection

• Strategies for enrolling patients in clinical trials

• Larger cadre of clinical investigators and clinical trial infrastructure to support an expanded national and international program of interventional clinical trials for IBD

• Greater public awareness and understanding of IBD through public educational programs

• Clinical summit of investigators, all stake holding agencies, and industry