IGEM:Stanford/2009/Meetings/5/13/09

Wednesday, May 13

Ariana: Treg and Th17 development and signaling pathways

Mark: tryptophan promoters--please take a look at the Biobrick parts identified in the powerpoint presentation. Specifically, at what concentrations do these promoters function? What exactly is the mechanism behind their interaction with trp--do they interact solely with trp or is there an indirect mechanism? -Additional information on trp attenuation

Anusuya: tryptophan and Indoleamine 2,3-dioxygenase (IDO): What are the numerical values of trp concentrations in environments of immunosuppression? Please take a look at what concentrations of trp this enzyme functions and to what extent its expression fluctuates in Tregs in response to changes in the local environment. Ming: Please read the following article about the relationship between Th17 cells and gut flora-derived ATP. I skimmed it earlier, and I thought it suggested that the relationship between ATP and Th17 induction may be more complex than it seems. Please clarify on this for the group, so that we can discuss whether modifying extracellular ATP production is a viable method of increasing Th17 cell counts. http://www.nature.com/nature/journal/v455/n7214/full/nature07240.html

Leon: The following article discusses the regulation of Th17/Treg balance through gut flora DNA. Please take a look at this article (don't worry about details--I would recommend the introduction and conclusion mainly) and present salient points to the team. Also, can you find any specific sequences from commensal bacteria in the human gut that stimulates TLR9 specifically? http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSP-4TK96M8-4&_user=145269&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000012078&_version=1&_urlVersion=0&_userid=145269&md5=b95b88aa65f763597a31b3c5ce3d9ec8

Robert: prostaglandin E2 (PGE2)--what exactly is the nature of PGE2--small molecule, protein, etc. I didn't have time to read this article in full, but when I skimmed it I became concerned because I thought it suggested that the TRBIII promoter is regulated only indirectly by PGE2. If this is so, can you find a different promoter (preferably naturally occurring in bacteria) that responds directly to PGE2? Otherwise, if PGE2 directly interacts with the promoter, then what are its basal concentrations in blood and human tissue and what are its precise (numerical) concentrations in inflamed synovial tissue?

Suzie: Nitric oxide is known to be produced by Th17 cells. Please look into the pathway involving the soxS/soxR pathway, particularly focusing on how the presence of nitric oxide modifies soxR protein and subsequently affects the soxS promoter. The following article may or may not be useful: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1169705 Check this out http://www.pubmedcentral.nih.gov/pagerender.fcgi?artid=47699&pageindex=1#page Activation by nitric oxide of an oxidative-stress response that defends Escherichia coli against activated macrophages. Some Notes from these articles Notes from Papers.doc

Michael: Please clarify the exact mechanisms by which retinoic acid abrogates Th17 expansion and supports commitment to the Treg lineage. What specific molecules are involved in this process? Also, what is the basal concentration of retinoic acid in human blood and tissue? Also, please look into beta-Carotene 15,15'-Dioxygenase, the product of the blh gene (see powerpoint slide 12 for more details). At what point in the process of vitamin A synthesis does this enzyme act?

Bobby: Please read the following brief article: http://www3.interscience.wiley.com/journal/122254996/abstract and comment to the team about what other molecules are good candidates for disruption of Th17 differentiation. In particular, are there ways that we could take advantage of Th17/Treg sensitivity to the aryl hydrocarbon receptor, or are its effects too complex (you will probably have to look further than this article to answer this last question.)