This proposal is a renewal application of the revised R01 grant funded for two years under the NIH American Recovery Reinvestment Act (ARRA). This grant, funded from July 15, 2009 to June 30, 2011, has led to elucidation of a series of fundamental principles concerning the role of IL-15 in EE pathogenesis. This renewal application seeks to extend our basic and translational analysis of EE, aimed at uncovering the role of IL-15 and IL-15-responsive cells in the regulation of esophageal eosinophilia in human EE. In the first cycle of this two-year R01 grant, we identified several key molecules that are directly responsible for the initiation and progression of EE pathogenesis in experimental models and have developed evidence that these findings apply to human EE. The details of our findings are presented in the progress report. In brief, we have demonstrated induced IL-15 mRNA/protein and iNKT cells in the esophageal biopsies of human EE and provided evidence that IL-15 and iNKT cells have a critical role in the initiation and progression of aeroallergen- o food allergen (peanut)-induced experimental EE. Therefore, in the extended cycle of grant tenure, we propose to test the central hypothesis that chronic IL-15 expression leads to the development of IgE- associated EE pathogenesis and that receptors, chemokines, and surface molecules of IL-15- responsive cells are the potential diagnostic and therapeutic targets molecules for human EE. The three specific aims will test our central hypothesis. In the first aim,we will test several sub-hypotheses concerning the role of IL-15 in the induction of mast cells; B cell growth, activation, and proliferation; and the mechanism of Ig class switching in EE by examining the esophageal transcript profile of IL-15 overexpression mice. Correlation of IL-15 with the presence of esophageal furrows, rings, and stricture in human EE will also be examined.
The second aim will test the hypothesis that IL-15 and cell surface molecules and chemokines of IL-15-responsive cells may be novel diagnostic biomarkers for human EE. We will test several related sub- hypotheses concerning the mRNA and protein levels of IL-15, IL-15R , IgE, CD1d, V 24, and CXCL16 in the blood of normal individuals and patients with gastroesophageal reflux disease (GERD) and EE. In the third aim, we propose a set of experiments designed to test several related primary hypotheses focused around iNKT cells and IL-15 being novel target molecules for EE therapy. Our studies are timely given the recent attention that EE is receiving in the medical community.
Eosinophilic esophagitis is a recently recognized inflammatory esophageal disorder. While it is being increasingly diagnosed; the etiology of the disease pathogenesis is not yet clearly understood. The goal of the present proposal is to investigate a novel mechanistic pathway based on IL-15 overexpression and induction of IL-15-responsive cells in the esophagus in order to provide a better understanding of EE and novel diagnostic biomarkers and therapeutic target molecules for human EE.
|Mussarat, Ahad; Manohar, Murli; Verma, Alok K et al. (2018) Intestinal overexpression of interleukin (IL)-15 promotes tissue eosinophilia and goblet cell hyperplasia. Immunol Cell Biol 96:273-283|
|Sandersa, Nathan L; Venkateshaiah, Sathisha Upparahalli; Manohar, Murli et al. (2018) Interleukin-18 has an Important Role in Differentiation and Maturation of Mucosal Mast Cells. J Mucosal Immunol Res 2:|
|Venkateshaiah, Sathisha Upparahalli; Zhu, Xiang; Rajavelu, Priya et al. (2018) Regulatory effects of IL-15 on allergen-induced airway obstruction. J Allergy Clin Immunol 141:906-917.e6|
|Manohar, Murli; Verma, Alok K; Venkateshaiah, Sathisha Upparahalli et al. (2018) Role of eosinophils in the initiation and progression of pancreatitis pathogenesis. Am J Physiol Gastrointest Liver Physiol 314:G211-G222|
|Venkateshaiah, Sathisha Upparahalli; Mishra, Akanksha; Manohar, Murli et al. (2018) A critical role for IL-18 in transformation and maturation of naive eosinophils to pathogenic eosinophils. J Allergy Clin Immunol 142:301-305|
|Verma, Alok K; Manohar, Murli; Venkateshaiah, Sathisha Upparahalli et al. (2018) Role of Vasoactive Intestinal Peptide in Promoting the Pathogenesis of Eosinophilic Esophagitis (EoE). Cell Mol Gastroenterol Hepatol 5:99-100.e7|
|Manohar, Murli; Verma, Alok Kumar; Venkateshaiah, Sathisha Upparahalli et al. (2017) Pathogenic mechanisms of pancreatitis. World J Gastrointest Pharmacol Ther 8:10-25|
|Manohar, Murli; Verma, Alok K; Upparahalli Venkateshaiah, Sathisha et al. (2017) Food-Induced Acute Pancreatitis. Dig Dis Sci 62:3287-3297|
|Verma, Alok K; Manohar, Murli; Upparahalli Venkateshaiah, Sathisha et al. (2017) Neuroendocrine cells derived chemokine vasoactive intestinal polypeptide (VIP) in allergic diseases. Cytokine Growth Factor Rev 38:37-48|
|Manohar, Murli; Verma, Alok K; Venkateshaiah, Sathisha Upparahalli et al. (2017) Chronic Pancreatitis Associated Acute Respiratory Failure. MOJ Immunol 5:|
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