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. 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? Requirements for the oral presentation - presenter

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 Laboratory http://blumberg-serv.bio.uci.edu http://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. half-site recognition half-site spacing dimerization ligand-binding transcriptional activation dimerization Nuclear Hormone Receptors - A Large Family of Ligand Modulated Transcription Factors DNA-binding AGGTCA n DIEDIE

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. EX-Orphans RAR α,β,γall-trans retinoic acid RXR α,β,γ 9-cis retinoic acid PPAR α,β,γ fatty acids, eicosanoids LXR α,βoxy-sterols FXR α,β bile acids BXR α,βbenzoates Nearly EX-orphans (natural ligands?) CARandrostanes, xenobiotics SXR/PXRsteroids, xenobiotics Orphan Receptors VertebrateDrosophila TR-2 α,βDHR78 NGFI-B α,β,γ DHR38 ROR α,β,γ DHR3 Rev-erb α,βE75, E78 SF-1 α,βFTZ-F1 α,β COUP α,β,γ svp HNF-4 α, βHNF-4 Tlx α,βtll No known homologs ERR α,β,γknirps DAX-1 knirps-related SHP egon GCNFDHR96 C. elegans~250 nuclear receptors D. melanogaster~20 nuclear receptors H. sapiens~48 genes Arabidopsisno family members The Nuclear Hormone Receptor Superfamily Known Receptors Classical receptors (from biochemistry) GRcortisol MRaldosterone AR α,βtestosterone PR α,β progesterone ER α,β estradiol VDR1,25-(OH) 2 vit D3 TR α,βtriiodothyronine EcR20-OH ecdysone