National Commission on Digestive Diseases Chapter 8: Diseases of the Stomach and Small Intestine - PowerPoint PPT Presentation

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National Commission on Digestive Diseases Chapter 8: Diseases of the Stomach and Small Intestine

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Conduct clinical trials for acute diarrhea ... Mutual funding of multicenter trials for therapies of NEC ... Conduct clinical trials to compare multimodality ... – PowerPoint PPT presentation

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Title: National Commission on Digestive Diseases Chapter 8: Diseases of the Stomach and Small Intestine


1
National Commission on Digestive Diseases
Chapter 8 Diseases of the Stomach and Small
Intestine
  • Chair Eugene B. Chang
  • Vice-Chair Maurice Cerulli

2
Background and IntroductionGastric and Small
Bowel Disorders
  • Overview Three major groupings
  • Acid/peptic disorders
  • Diarrheal diseases, Malabsorption, maldigestion
  • Celiac disease and others (including pediatric
    disorders)

3
Research Goal 1improve treatment of H. pylori
acid-peptic diseases, OBJECTIVES
  • Profile the microbial, molecular, cellular and
    epidemiological features of H. pylori induced
    gastric carcinogenesis and PUD
  • Identify diagnostic, prognostic, predictive,
    preventive and therapeutic targets
  • Define relationship between HP GERD
  • Assess prolonged proton-pump inhibitor use
  • Develop noninvasive tests for HP induced
    premalignant lesions
  • Develop prevention strategies for cancers

4
Research Goal 2Reduce and prevent NSAID peptic
diseases
  • Define pathogenic mechanisms of NSAID induced
    injury
  • Population based screening pharmacogenomic
    approaches to identify at risk pts
  • Educate patient MDs regarding risk factors
    improve adherence to appropriate strategies to
    decrease NSAID GI complications

5
Research Goal 2 NSAIDs (continued)
  • Determine long term risk for chronic NSAID usage
    PPI therapy, including risk of neoplasm
  • Design anti-inflammatory agents of comparable or
    higher efficacy to traditional NSAIDs without GI
    side effects and cardiovascular toxicity

6
Research Goal 5
  • Determine the genetic, molecular, and
    integrated physiological bases of intestinal
    water, nutrient and electrolyte transport

7
Research Goal 6
  • Improve treatment, prevention, and diagnosis of
    malabsorptive and diarrheal diseases

8
Research Goal 6 Objectives
  • Determine the causes of chronic diarrheal
    diseases in 40 of pts in which no specific cause
    is identified (some will be due to polymorphisms
    and/or mutations in intestinal transporters).
  • Develop preventative measures to limit the
    incidence of acute diarrheal diseases. Evaluate
    the role of non-hydrolyzable starch based ORS in
    treatment of acute diarrhea in adults and
    children in developing countries and in the US

9
Research Goal 6 Objectives (continued)
  • Develop clinically useful imaging diagnostic
    techniques to examine digestive processes
    abnormalities in diarrheal malabsorptive
    diseases
  • Test new anti-Cl secretory and pro-Na absorptive
    drugs in animal models of acute diarrheal
    diseases. Conduct clinical trials for acute
    diarrhea
  • Develop gene therapy targeting intestinal
    epithelial cells and pharmacologic agents capable
    of blocking or augmenting pathways that control
    intestinal gene expression as part of future
    treatment strategies for chronic diarrheal and
    malabsorptive/maldigestive diseases

10
Research Goal 7
  • Understand pathogenic mechanism of celiac
    disease and related autoimmune diseases

11
Research Goal 7 Objectives
  • Define the early innate events and the interplay
    between innate and adaptive immunity in celiac
    disease pathogenesis
  • Elucidate the events leading to transglutaminase
    activation and define its role in celiac disease
    pathophysiology both as an autoantigen and as a
    modifier or toxic gluten peptides
  • Define mechanisms and events that link the
    generation of large gluten peptides and the
    ultimate development of pathogenic T cell
    populations

12
Research Goal 7 Objectives (continued)
  • Define the role of antibodies and immune
    complexes in celiac disease
  • Define patterns in intestinal microbiome relevant
    to celiac disease and autoimmune/allergic
    disorders of the bowel
  • Define signaling pathway (eg protease, enteric
    toxins, cytokines) that are involved in the
    regulation of intestinal permeability under
    physiological and pathophysiological conditions
  • Distinguish between the effects of IL-23 and
    IL-12 in the pathogenesis of chronic inflammation

13
Research Goal 8
  • Improve screening, diagnosis, prevention, and
    treatment of celiac disease and of autoimmune and
    allergic disorders of the bowel. Characterize
    and define the mechanism underlying the
    association of celiac disease with autoimmune and
    neurological diseases

14
Research Goal 8 Objectives
  • Develop a more complete understanding of the
    pathogenesis of celiac disease, including the
    role of immune, epithelial, microbiological,
    environmental, and host factors as well as its
    relationship to other autoimmune diseases
  • Identify novel biomarkers, including additional
    genetic risk factors, to predict the development
    of autoimmune disease in high risk patients and
    to determine severity of illness and response to
    treatment

15
Research Goal 8 Objectives (continued)
  • Identify environmental triggers of celiac disease
  • Identify new, non-invasive methods to diagnose
    celiac disease
  • Develop non-dietary methods to treat celiac
    disease

16
Research Goal 9
  • Understand the pathogenesis of NEC and the unique
    susceptibility of the preterm infant, including
    genetic susceptibility , microbiome and
    immune/inflammatory processes

17
Research Goal 11
  • Determine the genetic bases, mechanism, natural
    history, clinical phenotypes of EGIDS and
    identify/develop novel therapeutic compounds

18
Research Goal 11 Objectives
  • Define the genetic bases, epidemiology and
    natural history of EGIDS
  • Define clinical phenotypes of EGIDS (e.g.
    allergic, non-allergic, or autoimmune) and
    develop novel animal models and reagents to study
    eosinophilic gastrointestinal inflammation
  • Define cellular molecular pathways that
    regulate eosinophil-dependent tissue remodeling

19
Research Goal 11 Objectives (continued)
  • Identify and develop novel agents for treatment
    of EGIDS such as anti-IL-5 antibody, anti-CCR3
    receptor antibody, and imatimib

20
Major Challenges to Achieve Goals
  • Animal models
  • Clinical research collaboration
  • Central research resources
  • Physician communication and education
  • Innovative technologies
  • Drug development

21
Major Challenges to Achieve Goals
  • Animal models
  • Experimental models that replicate human disease
    include H. pylori-induced gastric cancer and ZES,
    intestinal transport, malabsorption
    maldigestion, celiac disease, autoimmune
    allergic disease of bowel NEC
  • Animal models to study infection, morphologic
    interpretation of lesions, imaging technology,
    basic cellular processes such as endocytosis,
    migration ion transport in intestine and drug
    testing
  • Related resources
  • Improved organ cultures
  • Organotypic culture technologies
  • H. pylori strain repositories

22
Major Challenges to Achieve Goals
  • Clinical Research Collaboration
  • Multicenter, systems biology based consortia or
    networks of healthcare professionals to share
    materials information and increase statistical
    power
  • Interdisciplinary, population based, endoscopic,
    multi-institutional studies to identify HP
    infected populations at greatest risk for gastric
    cancer and to determine the prevalence and
    natural history of pre-malignant lesions
  • Multicenter networks to coordinate research and
    management of diseases that include rare gastric
    tumors, ZES, dyspepsia, chronic diarrheal
    malabsorptive diseases, NEC, celiac disease, and
    eosinophilic gastroenteritis
  • Small conferences for clinical scientific
    interactions that could spark innovative
    approaches

23
Major Challenges to Achieve Goals
  • Clinical Research Resources
  • Centralized resources, such as databases, patient
    registries biosample repositories
  • Databases with an emphasis on enrollment of
    minority gastric cancer patients and specimen
    tissue banks
  • Large scale biology approaches to identify
    protein-protein interactions, pH Ca homeostasis
    during digestion and in diarrheal diseases in Na
    absorptive, Cl secretory enteric endocrine
    cells
  • Repositories of clinical data samples from
    celiac disease, eosinophilic gastroenteritis,
    autoimmune pts or such high incidence families

24
Major Challenges to Achieve Goals
  • Physician Communication Education
  • Small conferences to promote interactions between
    adult pediatric clinicians to define the
    natural history of these diseases
  • Programs to determine cause of poor adherence to
    guidelines, make appropriate recommendations,
    develop mechanisms to disseminate
    recommendations, assess whether recommendations
    are being followed, assess alterations to
    outcomes (quality of care) for acid-peptic
    disease
  • Educational campaign to increase awareness of
    celiac disease among health care professionals

25
Major Challenges to Achieve Goals
  • Innovative Technologies
  • Experimental tools models to study intestinal
    epithelial physiology diseases, including
    diarrhea, malabsorption, development,
    inflammation pediatric diseases
  • Infrastructure to develop proteomics approaches
    to the study of GI disease
  • Methods to target epithelial cells/GI tissues
    sRNA or expression vectors or integrative models
    of gut absorptive digestive function in humans
  • Communication between basic scientists developing
    the technology for microbial ecology clinical
    scientists who are able to bring them to the pt
  • Genomic proteomic technologies to identify
    biomarkers using human intestinal samples

26
Major Challenges to Achieve Goals
  • Drug Development
  • Collaboration between academia the
    pharmaceutical biotech industries
  • High throughput screening of anti-diarrheal drugs
    that inhibit Cl secretion and/or stimulate Na
    absorption
  • Collaboration with industry to develop specific
    microbes (probiotics) or microbial products that
    stabilize the intestinal mucosal immune system
  • Mutual funding of multicenter trials for
    therapies of NEC

27
Chapter 11 Diseases of the Liver and Biliary
System
  • Chair Bruce R. Bacon, M.D.
  • Vice-Chair Maurice Cerulli, M.D.

28
Research Goal 2
  • Liver Cell Injury, Inflammation, Fibrosis and
    Repair (action plan, chapter 2)
  • Understand the cellular mechanism of liver
    injury, inflammation, repair and fibrosis and
    develop effective means for monitory and treating
    diseases caused by these processes

29
Research Goal 5
  • Viral Hepatitis (action plan, chapter 5)
  • Develop practical, safe, and effective means of
    prevention, treatment and control of the five
    forms of viral hepatitis

30
Research Goal 6
  • Viral Hepatitis (action plan, chapter 5)
  • Develop safe, and effective means of prevention,
    treatment and control of the five forms of viral
    hepatitis

31
Research Goals 5-8 Objectives
  • Viral Hepatitis (action plan, chapter 5)
  • Develop a vaccine or specific means of prevention
    of hepatitis C
  • Develop safer more effective means of treating
    chronic hepatitis C that can be applied to all
    categories of patients

32
Research Goals 5-8 Objectives (continued)
  • Viral Hepatitis (action plan, chapter 5)
  • Better understand the structure replication
    cycle of HCV for new therapeutic targets, better
    small molecule therapies
  • Better understand the host HCV interactions
    that determine viral clearance vs persistence
    (poor response in African- Americans)

33
Research Goals 5-8 Objectives (continued)
  • Viral Hepatitis (action plan, chapter 5)
  • Better understanding of the pathogenesis of HBV
    in all its forms (acute, chronic, active,
    inactive)
  • Better define the optimal means of treatment of
    chronic HBV
  • Conduct clinical trials to compare multimodality
    therapies for HBV

34
Research Goal 9
  • Non-alcoholic Fatty Liver Disease (action plan,
    chapter 7)
  • Better understanding of the pathogenesis of
    alcoholic and non-alcoholic liver disease
  • Develop noninvasive means to distinguish
    steatosis steatohepatitis
  • Identify test safe effective means of
    treatment of both forms of NAFLD
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