Role of acid sphingomyelinase in bronchial asthma

• Applicant: Dr. Eva Verjans
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 313698148

The acid sphingomyelinase (ASM) is one of the enzymes that catalyzes important reactions of the sphingolipid metabolism. Its deficiency causes the neurodegenerative Niemann-Pick disease, a lysosomal accumulation disease, in which patients exhibit neurological deficits as well as pulmonary infections or intermittent episodes of obstructive dyspnea. Previous studies demonstrated the influence of ASM on pulmonary edema formation in acute lung injury. Additionally, clinical trials revealed the potential effect of ASM-inhibitors as therapeutic target in patients with cystic fibrosis. As the role of ASM in bronchial asthma is completely unknown we addressed the topic in this study.Preliminary studies in our lab demonstrated a protective role of ASM-deficiency in a murine model of allergen-induced asthma with a clear downregulation of TH2-cytokines. In the context of this proposal we would like to study ASM-deficient mice in detail in a model of acute and chronic bronchial asthma. Thereby, it has to be defined, if the ASM-dependent regulation of immunological cells is significantly involved in the development of an asthmatic phenotype. In addition, this immunological relevance of ASM should be demonstrated with bone marrow chimeras.During the further experiments, we clearly want to define the immunological cell types, which ASM-dependent influence asthmatic disease activity. In vitro differentiations of T lymphocytes and antigen-presenting cells of ASM-KO and wildtype animals should help to identify the ASM-dependent cellular phenotype and the cytokine production of these cells. To clearly identify T cells as global ASM-regulated player, CD4+ T lymphocytes of ASM-KO animals will be transferred into RAG1-KO mice. If T cells appear to be only a secondary regulated cell type, we will focus on the ASM-regulation of antigen-presenting cells. We plan to generate a RAG1-ASM-double-knockout-mouse, which helps us to study the asthmatic inflammation independent of lymphocytes.The third aim of this study is to develop new therapeutic strategies in bronchial asthma based upon an inhalation of ASM-inhibitors like amitriptyline or fluoxetine. We would distinguish between two concepts: The preventive therapy, beginning with an ASM-inhibition starting previous to sensitization, and the therapeutic concept, with an ASM-inhibition next to allergen-provocation. If one of these strategies will be effective, we could demonstrate a new, potentially treatment of bronchial asthma.Summing up, this study should clearly define the immunological role of ASM in asthma and should provide first evidence for new therapeutic strategies with inhalations of ASM-inhibitors.

• DFG Programme: Research Grants