BioSci 2B - Environment and Human Health

1. BioSci 2B - Environment and Human Health • Bruce Blumberg • 2113E McGaugh Hall – open office hours • phone 824-8573 • blumberg@uci.edu • check e-mail and noteboard daily for announcements, etc.. • If you do not have ready access to e-mail or the web speak with me ASAP • Please use the course noteboard for discussions of the material

2. Introductions and Goals • Let’s introduce each other • Name • Major • Favorite thing about UCI • Least favorite thing about UCI • On a 3 x 5 card write • a sentence or two describing what you want to get out of this class • Times you are free to meet with me for 30 minutes next week

3. Rules for freshman seminars • Attendance • at least 8/10 lectures • Participation • Make a presentation • Participate in discussions • Be involved in your own education

4. Requirements for the oral presentation - presenter • Powerpoint presentation on a topic related to the environment and human health • Please approve it with me in advance • Send out links to the articles, web sites, etc in advance • 30 minutes with time allowed for discussion (max of ~20 slides) • What is the problem of interest – the big picture question • Present background – what is known, what is unknown • Present the story, research, etc • Present an analysis of the story or article • Which parts are credible • Which are suspect • How would you study the problem • Point out a few papers for further reading (reviews, followups, etc)

5. Requirements for the oral presentation - presenter • Logistics • Prepare presentation and either e-mail to me or bring it on a • CD-ROM • Floppy disk • USB flash memory drive • Or bring your own laptop • Bring light snacks for everyone – I will pay up to $20/class • I would like to post these on course web site – is that OK?

6. Requirements for the oral presentation listener • READ THE PAPER or article • Think about it – make notes on parts you have questions about • Listen to the speaker • If presentation is unclear, ask the speaker to elaborate • Always feel free to ask questions – we want an open discussion

7. Blumberg Laboratoryhttp://blumberg-serv.bio.uci.edu • The role of nuclear hormone receptors in: • development • physiology • endocrine disruption • cancer • Functional genomic approaches to: • identify cellular partners for known genes • define new members of signaling pathways • find downstream target genes • develop new drug targets

8. Nuclear Hormone Receptors - A Large Family of Ligand Modulated Transcription Factors ligand-bindingtranscriptional activationdimerization half-site recognitionhalf-site spacingdimerization DNA-binding AGGTCA n n n D I E

9. Nuclear Hormone Receptors • Bind to specific DNA targets - hormone response elements • Most activate transcription upon ligand binding • Some are constitutive • A few are deactivated by ligand binding • Ligands are small lipophilic molecules that freely enter cells • Diffuse from source • Penetrate to a target • Typically respond to low levels of hormone ~3 ppb (10-8 M) • Regulation of levels • Environmental agents

10. The Nuclear Hormone Receptor Superfamily Known Receptors Classical receptors (from biochemistry)GR cortisolMR aldosteroneAR α,β testosteronePR α,β progesteroneER α,β estradiolVDR 1,25-(OH)2 vit D3TR α,β triiodothyronineEcR 20-OH ecdysone Orphan Receptors Vertebrate DrosophilaTR-2 α,β DHR78NGFI-B α,β,γ DHR38ROR α,β,γ DHR3Rev-erb α,β E75, E78SF-1 α,β FTZ-F1 α,βCOUP α,β,γsvpHNF-4 α, β HNF-4Tlx α,βtll No known homologsERR α,β,γ knirpsDAX-1 knirps-relatedSHP egonGCNF DHR96 C. elegans ~250 nuclear receptorsD. melanogaster ~20 nuclear receptorsH. sapiens ~48 genesArabidopsis no family members EX-OrphansRAR α,β,γ all-trans retinoic acidRXR α,β,γ 9-cis retinoic acidPPAR α,β,γ fatty acids, eicosanoidsLXR α,β oxy-sterolsFXR α,β bile acidsBXR α,β benzoates Nearly EX-orphans (natural ligands?)CAR androstanes, xenobioticsSXR/PXR steroids, xenobiotics