Molecular studies on MYD88 alternative splicing in oncogenesis and Toll-like receptor 2 recognition of fungal chitin

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Dokumentart: PhDThesis
Date: 2020-01-01
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biologie
Advisor: Weber, Alexander (Prof. PhD)
Day of Oral Examination: 2018-07-13
DDC Classifikation: 500 - Natural sciences and mathematics
570 - Life sciences; biology
610 - Medicine and health
Keywords: Immunologie , Chitin , Toll-like-Rezeptoren
Other Keywords: TLR2
angeborene Immunität
innate immunity
Alternative splicing
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Toll-like receptors (TLRs) play critical roles in human innate and adaptive immune responses and although they are well characterized, there remain gaps in our understanding of the early events upon TLR activation. Here I present two different topics: first the regulation and function of MyD88 alternative splicing in B cell lymphomas and second, the role of the receptor TLR2 in the recognition of the very abundant natural agonist chitin. First topic: MyD88, a pivotal signaling protein for almost all TLRs, has been determined as an oncogenic driver in numerous cancers especially in Non-Hodgkin B cell lymphomas (B-NHL), and on the other hand, it has been found that the MyD88 gene undergoes alternative splicing. To date, five MyD88 isoforms were found in transcriptional analyses, but little is known about their natural occurrence and abundance in specific cell types. Furthermore, alternative splicing is often aberrant in cancers, resulting in novel protein isoforms which could originate or aid oncogenesis. In the present study, I evaluated the hypothesis that MyD88 alternatively spliced isoforms could be more highly expressed in B-NHL and might contribute to the well-studied oncogenic effect of MyD88. Second topic: Chitin is the second most abundant polysaccharide in nature and has been linked to fungal infection and allergic asthma. To date, several different receptors have been proposed to recognize chitin and evoke an inflammatory response. However, literature presents contradictory results and the physical binding of immune receptors to chitin has not been shown. Colleagues and I speculated that the discrepancies might be due to chitin’s highly polymeric nature and the use of crude extracts from crustaceans or fungi with variable purity as chitin preparations. Thus, we propose to use defined chitin (N-acetyl-glucosamine) oligomers comprising 4 to 15 subunits to overcome these limitations and identify the still unknown chitin-receptor.

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