Remote Instrumentation Access for the Ohio Consortium for Metabonomics

1. Remote Instrumentation Access for the Ohio Consortium for Metabonomics Aaron Goodpaster and Michael A. Kennedy Miami University, Ohio Department of Chemistry and Biochemistry Bioscience Cluster Expansion Guidelines Columbus, Ohio April 4, 2008

2. The Eminent Scholar Laboratory • Nuclear Magnetic Resonance Spectroscopy • X-ray Crystallography • HPLC-Mass Spectrometry • National Collaborative Project on Structural Genomics • The National Institutes of Health’s Protein Structure Initiative • Traditional Structural Biology Research • Focus on Human Diseases - DNA Repair • Metabolism in Exotic Bacteria • Protein Crystallography Studies • A State-Wide Consortium for Metabonomics • The Ohio Consortium for Metabonomics Studies of Children’s Diseases

3. The Eminent Scholar NMR Facility

4. Miami University: Eminent Scholar Laboratory Renovation

5. 600 MHz NMR at Miami University

6. Bruker Daltonics Agilent-MicrOTOF HPLC-Mass Spectrometer

7. Bruker AXS MicroStar ProteumR Single Crystal Diffractometer

8. Structural Genomics Goal “to make the three-dimensional structure of all proteins easily available from the knowledge of their corresponding DNA sequences”

9. Rutgers University • Guy Montelione - PI • Stephen Anderson • Swapna Gurla Columbia University • Wayne Hendrickson - Co-PI • Peter Allen • J. Eric Gouaux • Barry Honig • John Hunt • Burkhardt Rost • Liang Tong Ontario Cancer Institute • Cheryl Arrowsmith - Co-PI University of Toronto • Aled Edwards Co-PI • Igor Jurisica 10 Institutions Yale University • Mark Gerstein Co- PI • Lynn Regan Hauptmann-Woodward Medical Research Institute • George DeTitta - Co-PI Miami University (Pacific Northwest National Laboratory - through June 2006) • Michael Kennedy - Co-PI • John Cort • Theresa Ramelot • Keyang Ding SUNY Buffalo • Thomas Szyperski Cornell University- Weill Medical College • Hao Wu Mount Sinai School of Medicine • Ming-Ming Zhou

10. 40PNNL / NESG NMR Structures in PSI-1 1XPN 1NY8 1EIJ 1JYG 1NYN 1Q48 1XJS 1EIW 1R57 PSI-2 Miami - 60 Protein Structures 1SQR 1JI8 1SUO 1JW3 1X9B 1PUL 1JSB 1XPW 1M94 1JJG 1RZW 1NY4 1SOU 1XMO 1JRM 1LV3 1NEI 1NE3 1L7Y 1NXI 1E01

11. Metabonomics Studies of Human Diseases at 850 MHz Ohio Consortium for Metabonomics Studies of Children’s Diseases

12. Ohio Consortium for Metabonomics Studies of Children’s Diseases 20 collaborations on metabonomics studies of children’s diseases Metabonomics: Biomarker discovery for clinical diagnostics

13. Ohio Consortium for Metabonomics Studies of Children’s Diseases Initially targeting five clinical problems Cancer Heart disease Obesity Gastrointestinal Disorders Asthma and Allergy Cincinnati Children’s Hospital: Biliary atresia Inflammatory bowel disease Eosinophilic gastrointestinal disorders (EGID) Liver transplant rejection Kawasaki Disease Solid brain tumors Childhood Obesity Rainbow Babies Children’s Hospital: Brain tumors Columbus Children’s Hospital: Adolescent type I diabetes and vascular disease Neonatal necrotizing enterocolitis Genome Research Institute: Childhood Obesity

14. Metabonomics Study of Human Pancreatic Cancer Pancreatic cancer is the fourth leading cause of cancer death the in the USA More than 35,000 new diagnoses and deaths each year Five year survival rate is less than 3% When early detection is possible (<1 cm tumor), surgical resection has ~100% five year survival rate Obviously, most cases of pancreatic cancer go undetected until too late Urgent need for novel method for early detection of pancreatic cancer!

15. Preliminary Study of Two Mouse Models for Pancreatic Cancer Collaboration with Dr. Gloria Su at Columbia University 1. A model for human pancreatic intraepithelial neoplasias (PanIN) 2. A model for human mucinous cystis neoplasias (MCN)

16. Preliminary Study of A Mouse Model for Pancreatic Cancer Overlay of NMR Spectra of Urine Disease Model Control

17. Preliminary Study of A Mouse Model for Pancreatic Cancer PLS-DA Scores Plot disease control

18. Preliminary Study of A Mouse Model for Pancreatic Cancer The search for biomarkers for early detection of human pancreatic cancer PLS-DA - Loadings Plot

19. Distinguishing Ulcerative Colitis and Crohn’s Disease Crohn’s Disease (CD) • CD and UC • Major types of chronic inflammatory bowel disease (IBD) • Increased development of disease in developing countries • Cause of disease is unknown (both genetic and environmental factors) • Intestinal microflora plays a key role, those with IBD have an altered gut microbiota • CD • Can involve any part of the GI tract (mouth to the anus) • Affects the entire bowel wall • 26-199 cases per 100,000 people • UC • Generally restricted to the colon • Affects only the mucosa (inner lining) of the colon • 37-246 cases per 100,000 people Ulcerative Colitis (UC)

20. Distinguishing Ulcerative Colitis and Crohn’s Disease 100 Crohn’s samples - 40 UC samples - Ted Denson, MD CCHMC Child serum - Crohn’s 850 MHz Child serum - Crohn’s 600 MHz

21. Distinguishing Ulcerative Colitis and Crohn’s Disease Ted Denson, MD CCHMC 10 Crohn’s samples 10 Ulcerative Colitis samples Preliminary discovery of misdiagnoses?

22. Kennedy Research Group at Miami University Lindsey Aaron Miki Theresa Shuisong Keyang Romick Goodpaster Watanabe Ramelot Ni Ding Erik Feldman NESG: Gaetano Montelione Cheryl Arrowsmith Thomas Szyperski Aled Edwards NESG Members John Hunt Funding: National Institutes of Health Battelle Memorial Institute Department of Energy Environmental Molecular Sciences Laboratory Miami University undergraduates PNNL and WSU staff: Garry Buchko Amy Lindenberger Adam Ring John Cort Kate McAteer + 6 more