Projektbeschreibung
Stoffwechselprodukte von Darmbakterien auf dem Prüfstand
Das Mikrobiom im menschlichen Darm spielt für die Gesundheit eine zentrale Rolle und Änderungen in seiner Zusammensetzung lösen verschiedenste Krankheiten aus. Biosynthesegencluster könnten in der Struktur des Mikrobioms angelegt sein, doch bisher konnten nur bei wenigen die schädliche Wirkung auf den menschlichen Wirtsstoffwechsel experimentell validiert werden. Im EU-finanzierten Projekt SMs-Gut sollen diese ersten Erkenntnisse vertieft und spezialisierte Stoffwechselprodukte mit einer Schlüsselrolle bei der Entwicklung entzündlicher Darmerkrankungen und von Darmkrebs gefunden werden. Mit einer Kombination aus Bioinformatik, synthetischer Biologie und Analyseverfahren wird das Forschungsteam die biologischen Funktionen der entdeckten Verbindungen entschlüsseln.
Ziel
Composition changes of the human gut microbiome has been associated with a series of diseases. However, little is known about the mechanism of this microbiome alteration. Recent in silico studies revealed thousands of biosynthetic gene clusters (BGCs) that encode diverse types of specialized metabolites from human microbiomes. Many of these molecules are potentially involved in shaping microbiome structure or directly affect host cell and contribute to disease development. To date, only colibactin, a hybrid polyketide/non-ribosomal peptide produced by Escherichia coli in human gut, has been experimentally validated for its deleterious metabolic impact on human host and linked to the development of colorectal cancer (CRC). Thus, this project aims to expand the knowledge of specialized metabolites produced by gut microbiome and unravel their role in development of inflammatory bowel disease (IBD) and CRC. State-of-the-art bioinformatic, synthetic biology and chemical-analytic technologies will be used to tackle this challenge. In silico identification of BGCs will be facilitated by sequence homology search and the occurrence of function-related resistant makers. The cloning process will be realized by either capturing native BGCs, adopting polymerase amplification or using synthetic DNA, followed by HiFi DNA assembly, Red/ET recombineering based DNA integration method or combining of both strategies. The chemical diversity of these specialized metabolites will be unlocked by heterologous expression of the cloned BGCs and structure elucidation of the produced molecules. The biological functions of the discovered compounds will be established by probing their genotoxicity and cytotoxicity in vitro with human intestinal cell lines.
Wissenschaftliches Gebiet
- natural sciencesbiological sciencessynthetic biology
- natural sciencesbiological sciencesgeneticsDNA
- medical and health sciencesclinical medicinegastroenterologyinflammatory bowel disease
- medical and health sciencesclinical medicineoncologycolorectal cancer
- natural sciencesbiological sciencesmicrobiology
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Aufforderung zur Vorschlagseinreichung
Andere Projekte für diesen Aufruf anzeigenFinanzierungsplan
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Koordinator
01069 Dresden
Deutschland