Role of the PAPP-A/IGFBPs/IGF-1/-2 pathway in the pathogenesis of chronic rhinosinusitis with nasal polyp

• Applicant: Privatdozentin Dr. Sarina Müller
• Subject Area: Otolaryngology, Phoniatrics and Audiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 492894902

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic disease that is associated with high socioeconomical costs. Despite recent advances in the field of Rhinology, the pathogenesis remains elusive. In previous work of the applicant and her group, Pappalysin-1 (PAPP-A) was identified as a promising biomarker for cell proliferation in CRSwNP patients. PAPP-A has not been investigated before in CRSwNP but its connection to IGFBP/IGF, MEK/ERK and PI3K/Akt is known from other diseases. The central objective of this proposal is the investigation of the role of the PAPP-A/IGFBPs/IGF-1/- 2 pathway in the pathogenesis of CRSwNP as well as the identification of novel therapeutics for CRSwNP. The proposal is divided into three work packages (WPs) in order to reach the central objective. WP1 will characterize the PAPP-A/IGFBPs/IGF-1/-2 pathway in 2D undifferentiated epithelial and 2D fibroblast cell cultures. PAPP-A will be overexpressed, knocked down/knocked out and differences in selected proteins/mRNAs will be measured in CRSwNP and control patients. The majority of those proteins/mRNAs is pro-proliferative and is associated with the PAPP- A/IGFBPs/IGF-1/-2 pathway. Additionally, proliferation and vitality of the cells will be measured in the cell cultures. Consequently, the signaling of PAPP-A will be investigated and potential attack points for medication will be identified. In WP2, the important question of intercellular communication will be examined. The cell cultures of the control patients of WP1 will be used as a basis. Those cell cultures will be dosed with exosomes isolated from nasal mucus and from 3D air-liquid-interface (ALI) cell cultures of matching CRSwNP patients. The changes of the healthy cells after transfection with the pathological exosomes will be measured (proteins/mRNA of the PAPP- A/IGFBPs/IGF-1/-2 pathway and associated pathways, cell proliferation and vitality in the cell culture). In this WP, more insight about the intercellular communication will be gained and further important attack points for medication testing will be identified. WP3 will be based on the WP1 and WP2. The goal of the last WP is to identify a novel therapy that targets key players of the PAPP-A/IGFBPs/IGF-1/-2 pathway as well as to analyze complex interactions of the PAPP-A/IGFBPs/IGF-1/-2 pathway and other pathways that are important for CRSwNP. Medication testing in 3D ALIs and explant cell cultures will be performed for this WP (in primary CRSwNP polyp tissue, recurrent CRSwNP polyp tissue, control tissue). Explant cell cultures are defined as whole tissue pieces and resemble the physiological situation in vivo best. The effect of different medication on the PAPP- A/IGFBPs/IGF-1/-2 and associated pathways will be determined. This proposal will lead to an improved understanding of the pathogenesis of CRSwNP and to the identification of novel potential medication for the treatment of CRSwNP.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr.-Ing. Michael Döllinger