Human genome near complete: Oct. 21, 2004, Nature Sequencing SNPs HapMap Non-coding Sequence Histon-DNA, RNAi Pathway/Network Systems Biology Digital

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1 Genome-Omics-Pathway Network-Digital

2 Human genome near complete: Oct. 21, 2004, Nature Sequencing SNPs HapMap Non-coding Sequence Histon-DNA, RNAi Pathway/Network Systems Biology Digital Developmental Biology Digital Physiology

3 Pathway/Network Map/ Signal Transition Network

4 Pathway/Network : Gleeveck (imtinib mesylate) Novartis Abl(Abelson eukemia virus) Kinase 500, EGFR tyrosine kinase Iressa, Tarceva M.E.M. Noble,.. Science, 303, 19 March, 2004, pp

5 Putative pathways for immune drug discovery I3K P13K, AKT/PKB, PDK, PTEN, mtor, GSK3 Cancer rheumatoid arthritis, inflammation, respiratory disease APK yrosin inase (RTK ) ntegrin ronflammatory ntinflammatory hemokine -Cell, B-Cell ERK pathway: ERK1, ERK2, EGFR (RTK), HER2(RTK), B-RAF, MEK1, MEK2 JNK pathway: JNK1, JNKK P38 pathway: p38,,,, MAPKAPK2 EphB3, c-met, EGFR, HER2, VEGFR, FGFR, PDGFR, FLT3, Src, Lck AbI ILK, Integrin ( V/ 3, 2/ 1, 4/ 1) TNF-, TNF- receptor, TACE, IKK-,-,-, IL-1, IL-1R, IRAK1, IRAK2, IRAK3, IRAK4, IL-6, IL- 6R, Toll-like receptors, BlyS (BAFF), CD40L, LT-, GM-CSF IL-2, IL-2R, IL-4, IL-4R, IL10, IL-10R CXCR2, CCR3, CCR4, CCR5, CCR6, ERK, AKT, p38 TCR, calcineurin, IgE, FceRI, FceRII, kinases Inflammation, rheumatoid arthritis, cancer, and neurological diseases (Parkinson) Cancer, diabetes, rheumatoid arthritis/inflammation Inflammation, cancer, peripheral vascular disease, respiratory disease Rheumatoid arthritis and inflammatory disorders, autoimmune disorders, cancer Inflammation, cancer Cardiovascular disease, inflammation, infection, metabolic disease, respiratory disease, cancer Immune response, allergic disorders

6 : Genome Omics Transcriptomics Proteomics Metabon/lomics Protein-Protein Pathway Network Development Toxicity Disease Genome-Omics-Pathway/Network-Disease

7 Level Physiology Etiology Model Information Model Physical Exams. X-ray, MRI, ECG Tissue/Organ Cell Cellular Assays Path/Net Proteins Metabolites Chemical Analysis Genetic Test/Omics Genes

8 Integrated Biology Systems Biology Synthetic Biology Project Management

9 Omics Modeling/Simulation Data/Knowledge Base, Ontology, Semantic Net. Tutorial

10 NIH Roadmap Elias A. Zerhouni ( IBC's 9th Annual Drug Discovery Technology World Congress, ) New Pathways to Discovery - Building Blocks, Pathways, and Networks - Molecular Libraries and Imaging - Structure Biology - Bioinformatics and Computational Biology - Nanomedicine Research Teams of the Future Re-engineering the Clinical Research Enterprise

11 Job Market/Carrier Up Program

12 C.elegans (Caenorhabditis elegans) C,

13 Developmental Animation.elegans ell-lineage d positions RML & VA

14 Bioinformatics

15 CT l l

16 National Cancer Institute $12.6M/5years Todd Golub The Broad Institute/MIT & Dana-Faber Cancer Institute : kinase Cancer predictive model

17 : NR-SX Nuclear Receptor & Syndrome X Bioinformatics Success Story Equal Partnership

18 ADME/Tox

Arg394 Glu353 Leu525 His524 GLU353, HIS524, ARG394, LEU525, MET388, LEU391, ARG352 (kcal/mol) GLU353-39.

19 Arg394 Glu353 Leu525 His524 GLU353, HIS524, ARG394, LEU525, MET388, LEU391, ARG352 (kcal/mol) GLU HIS ARG THR GLU ILE ARG LEU MET

20 NR Feedback loop (Autocrine) Paracrine Hsp90 Hsp90 Dimerization Homodimer Heterodimer Cofactor Pathway/Network RNA splicing Translation Post transcriptional rodification TBP Response Element TATABox Target gene Polymorphism Gene expression Nuclear Receptors CYPs Transporters Other genes

21 NR IBAT: Acid Transporter, inos: Nitric oxidate sythase Ligands : FA Primary Genes NRs ER, TR, GR, PXR, CAR, LXR,VDR, PPAR, /, SREBP* Target Genes Proteins Pathway Transporters CYPs IBAT inos Function

22 NR ligands multi-hits Key-Lock Model Selective Nuclear Receptor Modulators Algorithm Omics

23 Adipokine Apo E Leptin Adiponectin Prostaglandin PAI-1 IL-6 TNF- androgen estrogen Adipocyte Resistin Visfatin PBEF) TGF Adipogenesis FFA

24 Pancrea Modeling Insulin Signaling Adipocytes cells glucose GLUT2 Insulin receptor glucose GLUT mitochondria K + GLUT4 ATP Ca ++ Liver Insulin release glucose Hepatic portal vein Insulin receptor Hepatic vein Muscle glucose GLUT2 Insulin receptor GLUT glucose glycogen GLUT4

25 Adiposity signals Leptin/Insulin Vessel Adipocyte CNS Food intake Liver Pancreas Muscle Energy metabolism Gastro intestine Physical activity

26 ATP: NH 2 O N C O O O CH N P O P O P O CH C 2 O O O O H H H H HO OH N N CH

27 Senser/Processor ATP Proton ATP APM Kinase Cascade Kinase Kinase

28 NR-SX NR-SX!

29 Network Perceptron/Adaline,Nerual Net, GA Neruoinformatics Modeling Realistic Model Vortex Model ( M.C. Roco and W.S. Bainbridge, Converging Technologies for Improving Human Performance Nanotechnology, Biotechnology, Information Tecnology, and Cognitive Science, NSF/DOC-sponsored Report (wtec.org/convergingtechnologies/report/nbic_report.pdf)

30 1. Algorithm 2. literacy 3. NR-SX Tutorial ( /Tutorial

31 Discovery Learning Project UT,P :Goal is To improve students ability as independent thinkers and life-long learners.(

32 NSF:The Role of Theory in Biological Physics and Materials (biophysics.asu.edu/workshop) Philip Nelson, Biological Physics-Energy, Information, Life, Freeman, NY, 2004 Internet : MIT

34 Carrier Up Program

< > Introduction to Basic Physical Chemistry 1,2 2 [ advanced [ [ [ [ [ KULASIS

< > Introduction to Basic Organic Chemistry 1,2 [ 2 [ 10 11 12 13 14 15 [ [ [ [ KULASIS < > Introduction to Basic Physical Chemistry 1,2 2 [ advanced [ 11 12 14 15 [ [ [ [ KULASIS < > Introduction to Basic