Mucosal Healing of the Intestinal Epithelial Barrier

Mucosal Healing of the Intestinal Epithelial Barrier

Tuesday, November 15, 2016

The New York Academy of Sciences

The intestinal epithelium is essential for human health. Increased permeability is associated with human diseases, including inflammatory bowel disease, ulcerative colitis, celiac disease, and irritable bowel syndrome, however whether this is an epiphenomenon, an early manifestation of disease, or a critical step in pathogenesis has been the subject of much debate.

In this symposium, we will evaluate the latest research investigating the benefits of achieving mucosal healing for the treatment of intestinal disorders. New insights into intestinal epithelial biology, assessment techniques, and the mechanisms underlying mucosal barrier dysfunction that could guide new therapeutic approaches, will be discussed.

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This event will also be broadcast as a webinar; registration is required.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City where possible.

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Agenda

* Presentation times are subject to change.


Tuesday, November 15, 2016

8:30 AM

Registration and Continental Breakfast

9:00 AM

Welcome and Opening Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Erick Young, PhD, Boehringer Ingelheim

9:20 AM

Tight Junction Barrier Loss: Friend or Foe?
Jerrold R. Turner, MD, PhD, Harvard Medical School

10:00 AM

Networking Coffee Break

10:30 AM

Epithelial Barrier Regulation by Inflammatory Bowel Disease Candidate Genes
Declan F. McCole, PhD, University of California, Riverside

11:10 AM

Cytokine-Mediated Regulation of Intestinal Inflammation: Beauty and the Beast
Tim Denning, PhD, Georgia State University

11:50 AM

Networking Lunch

1:00 PM

Immune-mediated Regulation of Epithelial Damage and Regeneration within the GI Tract
Alan Hanash, MD, PhD, Memorial Sloan Kettering Cancer Center

1:40 PM

Microbial Metabolites that Modify Intestinal Wound Repair
Thaddeus Stappenbeck, MD, PhD, Washington University School of Medicine

* Presenter slides will not be included as part of the Webinar broadcast.

2:20 PM

Networking Coffee Break

2:50 PM

Mucosal Barrier and Entero-hepatic Tissue Engineering
Linda G. Griffith, PhD, Massachusetts Institute of Technology

3:30 PM

Panel Discussion

4:15 PM

Closing Remarks
John Hambor, PhD, Boehringer Ingelheim

4:30 PM

Networking Reception

5:30 PM

Adjourn

Organizers

John Hambor, PhD

Boehringer Ingelheim

John E. Hambor is a director of the Research Beyond Borders division at Boehringer Ingelheim, where he coordinates a strategic postdoctoral research program focused on developing new therapeutic concepts in collaboration with academic investigators. He was previously a consultant with the Cell Therapy Group, the CEO of CellDesign, and a developer of stem cell technologies at Pfizer, where he worked on new drug targets for inflammation and immunology and developed stem cell-based assays for drug-efficacy and safety studies. Hambor received an MS in microbiology from Miami University of Ohio and a PhD in pathology from Case Western Reserve University. As a postdoctoral fellow at Yale University in the Department of Immunobiology, he researched the molecular basis of CD8 expression during T-cell development. He has been an adjunct assistant professor of immunology at Connecticut College since 2000. He also serves as a member of the board of directors for the Connecticut Veterans Administration Research and Education Foundation.

Erick Young, PhD

Boehringer Ingelheim

Erick R. Young obtained his PhD in synthetic bioorganic chemistry from Pennsylvania State University and completed postdoctoral studies in natural product synthesis at Ohio State University. He joined Boehringer Ingelheim Pharmaceuticals as a research project leader for immunology and cardiometabolic diseases. He became increasingly involved in the generation of new target concepts and novel therapeutic modalities for new target class spaces. He is currently director of external innovation for the newly formed Research Beyond Borders division, where his primary focus is the conception, identification, and enablement of new therapeutic mechanisms and disease indications outside the organization's current scope or capabilities.

Sonya Dougal, PhD

The New York Academy of Sciences

Caitlin McOmish, PhD

The New York Academy of Sciences

Speakers

Tim Denning, PhD

Georgia State University

Dr. Timothy L. Denning is a tenured Associate Professor at Georgia State University in the Institute for Biomedical Sciences. He earned his PhD degree in Microbiology and Immunology at the University of Texas Medical Branch in Galveston, TX and performed postdoctoral training at the La Jolla Institute and Emory Vaccine Center. Before joining Georgia State University, Dr. Denning was an Assistant Professor in the Department of Pediatrics and Department of Pathology and Laboratory Medicine at Emory University. His biomedical research has focused on the role of intestinal immune cells in the regulation of experimental models of Crohn's disease and ulcerative colitis. His high-impact research has been exceedingly productive as evidenced by over 45 peer-reviewed publications that have collectively been cited over 3,000 times. Given the importance of his studies, Dr. Denning has received continuous support for his research throughout his career in the form of NIH and Crohn's and Colitis Foundation of America awards. His outstanding research contributions are further evidenced by him being the recipient of numerous honors, awards, and lectureships both nationally and internationally. He serves as a grant reviewer for numerous agencies including NIH and is on the editorial board for the Journal of Immunology, Gastroenterology, and Inflammatory Bowel Diseases and is an ad hoc reviewer for numerous other journals. Dr. Denning is also an active member of the American Association of Immunologists, the American Society for Investigative Pathology and the Society for Mucosal Immunology where he serves as Treasurer.

Linda G. Griffith, PhD

Massachusetts Institute of Technology

Linda G. Griffith, PhD (UC Berkeley, Chemical Engineering), is the School of Engineering Teaching Innovation Professor of Biological and Mechanical Engineering and MacVicar Teaching Fellow at MIT, where she directs the Center for Gynepathology Research and the Human Physiome on a Chip Project supported by the DARPA/NIH-funded Microphysiological Systems Program. She led development of MIT's undergraduate major in Biological Engineering, which launched in 2005 as MIT's first new major in almost 40 years. She is a member of the National Academy of Engineering and her awards include a MacArthur Foundation Fellowship and the Popular Science Brilliant 10 Award. She has served as a member of two NIH Advisory Councils (NIDCR and NIAMS) and currently serves on the Advisory Committee to the Director of NIH.

Alan Hanash, MD, PhD

Memorial Sloan Kettering Cancer Center

Dr. Hanash is a physician-scientist and member of the Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center (MSKCC). His laboratory studies transplant immunology with an emphasis on interactions between the immune system and epithelial tissues. The Hanash lab utilizes hematopoietic transplantation as a clinically relevant model system for interrogating immunologic regulation of tissue damage and regeneration. He went to medical school and graduate school at the University of Miami, trained in internal medicine at the University of Chicago, and performed his oncology fellowship training at MSKCC. Dr. Hanash's work has described the role of group 3 innate lymphoid cells (ILCs) and Interleukin-22 (IL-22) in protection against intestinal pathology after hematopoietic transplantation, transcriptional regulation of ILCs, and damage to the intestinal stem cell compartment in graft vs. host disease. Recent work has shown that IL-22 from ILCs can act upon intestinal stem cells to stimulate epithelial regeneration.

Declan F. McCole, PhD

University of California Riverside

Dr. McCole obtained his PhD from the Department of Pharmacology and the Faculty of Veterinary Medicine, University College Dublin in 1997. He conducted postdoctoral research at the University of California, San Diego in the laboratories of Dr. Martin F. Kagnoff and Dr. Kim E. Barrett. He obtained a junior faculty appointment as a Project Scientist in 2004 and became an Assistant Professor of Medicine in 2009. In 2013 he was recruited from UCSD to join the new medical school at the University of California Riverside. His research focuses on regulation of intestinal epithelial barrier function in inflammatory bowel disease (IBD). His lab was the first to identify that the IBD candidate gene, PTPN2, protects intestinal epithelial barrier function from the effects of inflammation. In addition to researching potential therapies to enhance intestinal barrier function, his lab also investigates the role of the energy sensor, AMPK, in the regulation of epithelial barrier and electrolyte transport functions. He received the New Investigator Award from the GI & Liver Section of the American Physiological Society in 2011 and currently serves as Chair of that section.

Thaddeus Stappenbeck, MD, PhD

Washington University School of Medicine

Thaddeus Stappenbeck is currently the Conan Professor of Laboratory and Genomic Medicine and the Co-Chief, Division of Laboratory and Genomic Medicine in the Department of Pathology and Immunology at the Washington University School of Medicine. He received a BA degree in the Integrated Science Program from Northwestern University. He obtained and MD/PhD from Northwestern University. He trained in anatomic pathology at Washington University School of Medicine. Dr. Stappenbeck's research program has focused on the response of intestinal epithelial cells to injury using several mouse models including chemical and physical damage as well as genetic modulation of the immune system and epithelial function. His lab has found epithelial repair is directed by intestinal microbes, specific cells of the immune system and the stromal cells that support the epithelium. Within the intestinal epithelium, the process of autophagy is required within specific secretory cells to support intestinal homeostasis. His lab has been supported by the National Institute of Health, the Crohn's Colitis Foundation of America, The Broad Medical Research Program, the Helmsley Foundation, the Rainin Foundation and the Pew Foundation.

Jerrold R. Turner, MD, PhD

Brigham and Women's Hospital

Jerrold R. Turner, MD, PhD, is at Brigham & Women's Hospital and Harvard Medical School (Massachusetts, USA). He is an active gastrointestinal surgical pathologist, author of chapters in leading textbooks, and Editor-in-Chief of the new American Gastroenterological Association journal Cellular and Molecular Gastroenterology and Hepatology. Dr. Turner's research program, which has been continuously funded by the NIDDK since 1994, is focused on intestinal epithelial biology, with particular emphasis on tight junction regulation and inflammatory bowel disease. His group takes a multidisciplinary approach that integrates cell biology, transport physiology, electrophysiology, structural biology, molecular biology, and mucosal immunology to define fundamentals of structure and function; understand mechanisms of regulation in vitro and in vivo models; determine the contributions of barrier dysfunction to gastrointestinal disease; understand the role of the epithelial barrier in regulating other mucosal processes, e.g. immune responses; and develop novel means to correct barrier function and restore health. Major discoveries from his group include the central roles and regulation of myosin light-chain kinase in tight junction regulation, the nature of tight junction protein interactions, and molecular underpinnings of tight junction flux pathways.

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The Biochemical Pharmacology Discussion Group is proudly supported by:

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Abstracts

Tight Junction Barrier Loss: Friend or Foe?
Jerrold R. Turner, MD, PhD, Brigham and Women's Hospital, Departments of Pathology and Medicine (GI), and Harvard Medical School

The intestinal epithelial tight junction defines the paracellular permeability of non-ulcerated mucosae. Rather than an absolute barrier, the tight junction is a selectively permeable filter that can be modulated by both physiological and pathophysiological stimuli. Recent molecular and biophysical advances have defined two distinct trans-tight junction flux pathways, termed pore and leak, with different selectivities and capacities, as well as the non-selective unrestricted pathway that reflects epithelial damage. In vitro analyses have shown that the representative cytokines interleukin-13 (IL-13) and tumor necrosis factor (TNF) specifically enhance flux across pore and leak pathways by increasing expression of the tight junction protein claudin-2 or activating myosin light chain kinase, respectively. While distinguishable in vitro, tools to specifically assess flux across pore, leak, or unrestricted pathways are poorly developed and seldom used. This has led to confusion and errant interpretations of barrier loss in human disease and in vivo models. Work assessing these pathways, means to selectively measure and target them, and impact on intestinal infectious, immune-mediated, and toxic injury-related disease models will be discussed.

Epithelial Barrier Regulation by Inflammatory Bowel Disease Candidate Genes
Declan F. McCole, PhD, Division of Biomedical Sciences, University of California Riverside

Inflammatory bowel disease (IBD) is a multi-factorial condition characterized by elevated levels of pro-inflammatory cytokines such as TNF-α and IFN-γ. Genome-wide-association-studies (GWAS) have greatly expanded our understanding of the genetic contributions to IBD. Moreover, many of the identified genes have been shown to modulate various aspects of the intestinal barrier. Multiple GWAS have revealed that individuals with single nucleotide polymorphic mutations in the locus of the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene have an increased susceptibility to IBD. Loss-of-function mutations in PTPN2 are also associated with two other inflammatory diseases, Celiac disease and Type I diabetes. Interestingly, all of these conditions are associated with an increase in intestinal permeability prior to evidence of inflammation. We identified that the PTPN2 gene and its protein product, T-cell protein Tyrosine Phosphatase (TCPTP), play a crucial role in restricting the capacity of the IBD-associated inflammatory cytokine, interferon-gamma (IFN-γ) to induce barrier defects. This presentation will focus on the mechanisms by which TCPTP protects intestinal epithelial barrier function using knockout mouse models and novel epithelial cell lines lacking TCPTP or expressing mutated forms of PTPN2. This will include identification of specific epithelial tight junction molecular targets that are altered by TCPTP loss of activity, and approaches to restore a compromised epithelial barrier.

Cytokine-Mediated Regulation of Intestinal Inflammation: Beauty and the Beast
Tim Denning, PhD, Georgia State University

Several members of the IL-1 family of cytokines (IL-1α, IL-1β, IL-1Ra, IL-18, IL-33) are up-regulated in the inflamed mucosa during experimental colitis and human IBD and polymorphisms in the some of these genes correlate with increased susceptibility to ulcerative colitis or Crohn's disease. Classic IL-1 family cytokines are produced predominantly by macrophages following inflammasome activation and caspase-1-mediated cleavage of a pro-domain and have potent pro-inflammatory functions. Once secreted, these IL-1 family members are involved in activation of innate and adaptive immune cells, and regulation of the intestinal epithelial barrier and permeability. Collectively, these observations suggest that IL-1 family members may contribute to intestinal inflammation during IBD. More recently, five additional IL-1 family members have been identified. IL-1F5 (renamed IL-36Ra), IL-1F6 (renamed IL-36α), IL-1F8 (renamed IL-36β) and IL-1F9 (renamed IL-36γ) all bind to the primary receptor IL-1Rrp2 (renamed IL-36R), which allows recruitment of the coreceptor IL-1RAcP, and the subsequent activation of the NF-kB and MAPK pathways. IL-36 receptor antagonist (IL-36Ra) blocks signaling by IL-36α, IL-36β, and IL-36γ through a mechanism similar to IL-1Ra inhibition of IL-1α and IL-1β. Thus, IL-36 signaling appears to be tightly controlled to limit excessive inflammation. The contributions of the IL-36/IL-36R axis during experimental and human IBD are just beginning to emerge and recent advances will be discussed.

Immune-mediated Regulation of Epithelial Damage and Regeneration within the GI Tract
Alan M. Hanash, MD, PhD, Memorial Sloan Kettering Cancer Center

Immune-mediated injury to the gastrointestinal (Gl) tract is an important cause of morbidity and mortality, and it is a frequent cause of toxicity after allogeneic hematopoietic transplantation. There is currently little understanding of how bone marrow transplant (BMT) recipients recover from tissue damage due to graft vs. host disease (GVHD), where donor T cells attack recipient epithelial tissues including the GI tract. There is also little understanding of how immune-mediated intestinal injury affects the intestinal stem cell (ISC) compartment. We have identified that Interleukin-22 (IL-22) is an important regulator of GI regeneration post-transplant and that IL-22 from ILCs directly stimulates ISC-dependent epithelial regeneration in vitro. After damage, ILCs are activated to produce IL-22, and crypt epithelial cells increase their expression of the IL-22 receptor. These findings support the idea that after intestinal damage the immune system is activated to contribute to the ISC niche in order to promote recovery of the tissue and restore the integrity of the mucosal barrier. However, this regenerative axis is disrupted in GVHD, as donor T cells lead to the elimination of IL-22-producing ILCs and loss of the IL-22-mediated regenerative response. We have also found that Lgr5+ ISCs, which are capable of regenerating all intestinal epithelial cells, are depleted in GVHD and that IL-22 deficiency exacerbates the loss of ISCs in GVHD. Therefore, tissue damage in GVHD may represent a "two-hit" process, where donor T cells attack the GI tract as well as the immune cells protecting it and promoting its recovery.

Microbial Metabolites that Modify Intestinal Wound Repair
Thaddeus Stappenbeck, MD, PhD, Washington University School of Medicine, Saint Louis

The timing and efficiency of wound repair in the intestine is influenced by the microbiome. Previous studies show that germ-free or antibiotic-treated mice have poor responses to mucosal damage. When injured, the mucosa undergoes repair in defined phases, all of which are influenced by the microbiome. The initial phase of repair is characterized by the covering a wound site by highly mobile, squamous epithelial cells. These cells, also known as wound associated epithelial cells (WAE) are produced by stem cells within crypts adjacent to the injury site. WAE cells undergo adaptive reprogramming under the influence of prostaglandin E2. Once the WAE layer begins to form, a second phase of repair commences that is characterized by an expansion of epithelial stem cells that also emanate from crypts that are adjacent to injuries. The expanded stem cells form channels within the wound bed that are directed towards the center of the injury. The wound bed mesenchyme is also highly organized and coordinated. Specifically, populations of mesenchymal stem cells and macrophages appear at specific times and locations within the wound bed and are required for repair. Microbial antigens and metabolites interact with specific cell types within the wound during specific phases of repair. We have found that specific microbial factors can either positively and negatively influence the rate and extent of repair after injury. These factors and the host pathways they engage have provided new insights into mechanisms of wound repair in the intestine.

Mucosal Barrier and Entero-hepatic Tissue Engineering
Linda Griffith, PhD, Massachusetts Institute of Technology

"Mice are not little people"—a refrain becoming louder as the strengths and weaknesses of animal models of human disease become more apparent. At the same time, three emerging approaches are headed toward integration: powerful systems biology analysis of cell–cell and intracellular signaling networks in patient-derived samples; 3D tissue engineered models of human organ systems, often made from stem cells; and micro-fluidic and meso-fluidic devices that enable living systems to be sustained, perturbed and analyzed for weeks in culture. This talk will highlight the integration of these rapidly moving fields to understand difficult clinical problems, with an emphasis on translating academic discoveries into practical use for analysis of mucosal barrier tissue function, inflammation, and entero-hepatic interactions. Specifically, approaches for building complex 3D mucosal barrier models using synthetic extracellular matrix, along with synergistic interactions between intercommunicating gut and liver will be described.
 
Coauthors: Kelly Chen1, Victor Hernandez-Gordillo1, Murat Cirit1, Christi Cook1, Jorge Valdez1, Dave Trumper1, Collin Edington1, Gaurav Rohatgi2, David Hughes3, and Doug Lauffenburger1.
 
1. Massachusetts Institute of Technology
2. Continuum Innovations, Boston
3. CN Bioinnovations, London

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