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During research designed to develop a cholera vaccine in the late 1990s, I uncovered a toxin, zonula occludens, which causes diarrhea by loosening the tight junctions between enterocytes in the intestine, thus allowing intestinal permeability.
Subsequently, our lab identified the protein zonulin, which controls this process. We have since established the role of zonulin in the pathogenesis of celiac disease and type 1 diabetes.
We are currently investigating the composition and changes in the gastrointestinal microbiota to help determine why some individuals with an inherited predisposition to celiac disease develop clinical disease, while others do not.
We are also working to uncover a biomarker and to develop a diagnostic tool for non-celiac gluten sensitivity.
Our latest research includes a focus on how the gut microbiome is related to the development of autoimmune disorders.
Other current research projects include possible links between gluten-related disorders and conditions such as schizophrenia and autism spectrum disorder in certain subgroups of patients.
PRINCIPAL INVESTIGATORAlessio Fasano, MDDirector, Mucosal Immunology and Biology Research CenterDirector, Center for Celiac ResearchAssociate Chief for Basic, Clinical and Translational ResearchDivision Chief, Department of Pediatric Gastroenterology and NutritionVisiting Professor of Pediatrics, Harvard Medical School
RESEARCH STAFFKaren Lammers, PhD Lecturer, Pediatrics, Harvard Medical SchoolStefania Senger, PhDInstructor, Pediatrics, Harvard Medical SchoolMaureen Leonard, MD Instructor in Pediatrics, Harvard Medical SchoolClinical Director, Center for Celiac Research and TreatmentAssociate Investigator, Nutrition Obesity Research Center, Harvard Medical SchoolAnna Sapone, MD, PhDResearch Fellow in Medicine (Ext)Beth Israel Deaconess Medical CenterAlba Miranda-Ribera, PhDResearch Fellow
Rachel H. Freire, PhDPostdoctoral Researcher
Anil K. Verma, PhDPostdoctoral ResearcherGloria SerenaGraduate Research AssistantCraig SturgeonGraduate Research AssistantJingang LanResearch Laboratory ManagerShu YanResearch TechnicianLaura InganoResearch TechnicianStephanie CamhiClinical Research CoordinatorRosiane LimaClinical Research CoordinatorVictoria KenyonClinical Research Coordinator
Combining the disciplines of microbiology, molecular and cell biology, and physiology, Dr. Fasano’s research focuses on the crosstalk between enteric pathogens and their hosts. Through his earlier work Dr. Fasano has elucidated various intracellular signaling pathways that govern eukaryotic cell functions.
Through the discovery of a new enterotoxin named Zot (Zonula occludens toxin) in the late 1980s, Dr. Fasano and his colleagues began the study of the mechanism of action that involves the modulation of intercellular “tight junctions.” A series of seminal discoveries clarified that the paracellular space is not completely sealed, as previously believed, but is rather a sophisticated network of proteins forming tight junctions (TJ).
The discovery of Zot shed light on the modulation of TJ and led to the discovery of several other toxins that affect the paracellular pathway, opening new paradigms for bacterial pathogenesis.
Several years later, the Fasano team discovered zonulin, a Zot mammalian analogue involved in the regulation of TJ, and subsequently developed a zonulin inhibitor, Larazotide acetate. Safety and efficacy trials for the compound have been completed. The only late-stage drug with a “Path Forward” agreement with the FDA for the primary endpoint, dose and phase 3 trial design, Larazotide is scheduled for Phase 3 trials late in 2016. With this trajectory, Larazotide could be the first drug approved for patients with celiac disease as early as 2018.
The Fasano lab has a major research interest in the pathophysiology of the paracelluar pathway and the structural changes of cell cytoskeleton and TJ induced by zonulin, its prokaryotic analogue Zot, and gluten peptides.
Research conducted and reviewed by the Fasano group has linked many autoimmune diseases, including type 1 diabetes, multiple sclerosis, rheumatoid arthritis, ankylosing sponditis, IgA nephropathy, and inflammatory bowel diseases to the common denominator of aberrant intestinal permeability.
Current research directed by Dr. Fasano encompasses both basic science focused on bacterial pathogenesis, the gut microbiome and intestinal mucosal biology, and translational science focused on interventional clinical trials in autoimmune and inflammatory diseases, including celiac disease and asthma.
Researchers are looking at how qualitative or quantitative defects in the regulation of the immune system and the role of dysbiosis can lead to the onset and progression of celiac disease and other autoimmune disorders.
One objective of the Fasano lab is to understand the molecular mechanisms of the host’s functional and immune response to specific microorganisms.
This includes in-depth studies of bacteria-host interactions of three major gram negative bacterial human pathogens, including Helicobacter pylori, Salmonella enterica serovar Typhi, and Shigella dysenteriae-1, each primarily affecting a distinct major segment of the GI tract (i.e., the stomach, ileum and colon, respectively). Using new methodologies to study, in vitro and ex vivo, it is hoped that this interplay between microorganisms and host will shed light on clinical conditions in which this interplay may lead to disease status.
To date, there are no ideal animal models to recapitulate celiac disease in humans. To support the ultimate goal of reversing or preventing celiac disease and other autoimmune disorders, Dr. Stefania Senger has developed an innovative technique using intestinal tissue from people who have undergone clinically indicated endoscopies. She is engineering gut organoids to study the interaction between the gut tissue and the complex bacterial ecosystem in the intestine.
Through earlier work at the Center for Celiac Research at the University of Maryland School of Medicine, Dr. Fasano established that celiac disease affects approximately one percent of the U.S. population, a significantly higher number than previously believed.
In a large prospective study (www.cdgemm.org), the Fasano lab is currently investigating the composition of and changes in the gastrointestinal microbiota, along with environmental factors, to help determine why some individuals with an inherited predisposition to celiac disease develop clinical disease while others do not. International collaborators with the Fasano lab are also working to uncover a biomarker and to develop a diagnostic tool for non-celiac gluten sensitivity.
Dr. Fasano is also pursuing possible links between gluten-related disorders and conditions such as schizophrenia and Autism Spectrum Disorder in certain subgroups of patients.
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