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

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

The Eminent Scholar NMR Facility

Miami University: Eminent Scholar Laboratory Renovation

600 MHz NMR at Miami University

Bruker Daltonics Agilent-MicrOTOF HPLC-Mass Spectrometer

Bruker AXS MicroStar ProteumR Single Crystal Diffractometer

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

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 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 Institutions

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

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

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

Initially targeting five clinical problems 1.Cancer 2.Heart disease 3.Obesity 4.Gastrointestinal Disorders 5.Asthma and Allergy Columbus Children’s Hospital: 1.Adolescent type I diabetes and vascular disease 2.Neonatal necrotizing enterocolitis Genome Research Institute: 1.Childhood Obesity Ohio Consortium for Metabonomics Studies of Children’s Diseases Cincinnati Children ’ s Hospital: 1.Biliary atresia 2.Inflammatory bowel disease 3.Eosinophilic gastrointestinal disorders (EGID) 4.Liver transplant rejection 5.Kawasaki Disease 6.Solid brain tumors 7.Childhood Obesity Rainbow Babies Children’s Hospital: 1.Brain tumors

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!

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

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

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

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

Distinguishing Ulcerative Colitis and Crohn ’ s Disease 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 – cases per 100,000 people UC – Generally restricted to the colon – Affects only the mucosa (inner lining) of the colon – cases per 100,000 people Crohn’s Disease (CD) Ulcerative Colitis (UC)

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

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

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 Lindsey Aaron MikiTheresa Shuisong Keyang Romick Goodpaster Watanabe Ramelot Ni Ding Garry Buchko John Cort Kennedy Research Group at Miami University PNNL and WSU staff: Kate McAteer Adam Ring Amy Lindenberger + 6 more Erik Feldman undergraduates