Grant: Discovery Grants Program - Individual

Host immune responses are broadly divided into two branches: innate immune response and adaptive immune response. The innate immune response provides the first line defense against microbial infections and also guides the development of an appropriate adaptive response to clear the infection. In the case of immune disorders, inappropriate innate immune activation results in inflammatory responses that overwhelm the host and cause damages to the host. Innate immune activation is mediated by protein receptors such as Toll-like receptor 4. Molecules capable of interacting with these receptors hold great promise in delivering novel immuno-therapeutics for the treatment of diseases such as septic shock, bacterial infection, and cancers. In this proposal, we set out to create a group of molecules potentially able to bind to Toll-like receptor 4 and then investigate their biological activities either as immune activating agents or as immune modulating agents. One aspect of this research deals with molecules closely associated with the opportunistic bacterium Pseudomonas aeruginosa, which is the main cause for the chronic lung infection observed in cystic fibrosis (CF) patents. The conformational characteristics as well as supramolecular assembly of these molecules will be closely examined. Such investigation will provide a clearer picture about the structural requirement for their biological activities. Other aspects of this research are directed towards the generation and identification of molecules that display strong immune stimulating activities, or potent inhibitory effect against bacterial endotoxin. The findings from this interdisciplinary research will lead to a better understanding of the molecular mechanisms involved in pulmonary infection in CF patients, and may as well result in the identification of new chemical structures that show therapeutic potential for treating bacterial infection, cancers, and chronic inflammatory diseases.