Remote Instrumentation Access for the Ohio Consortium for Metabonomics

Aaron Goodpaster and Michael A. Kennedy

Miami University, OhioDepartment of Chemistry and Biochemistry

Bioscience Cluster Expansion GuidelinesColumbus, 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

1E011NEI

1Q48

1L7Y 1LV3

1NY4

1NY8

1NYN

1PUL

1RZW

1JI8

1NE3

1JSB

1SUO

1SOU1XPW

1XPN

1XMO

1M94

1NXI

1JYG1XJS

1SQR

1X9B

PSI-2Miami - 60 Protein Structures

Metabonomics Studies of Human Diseasesat

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 metabonomicsstudies of children’sdiseases

Initially targeting five clinical problems1. Cancer2. Heart disease3. Obesity4. Gastrointestinal Disorders5. Asthma and Allergy

Columbus Children’s Hospital:1. Adolescent type I diabetes and vascular disease2. Neonatal necrotizing enterocolitis

Genome Research Institute:1. Childhood Obesity

Ohio Consortium for Metabonomics Studies of Children’s Diseases

Cincinnati Children’s Hospital:1. Biliary atresia2. Inflammatory bowel disease3. Eosinophilic gastrointestinal disorders (EGID)4. Liver transplant rejection5. Kawasaki Disease 6. Solid brain tumors7. 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 ModelControl

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– 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

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 MontelioneCheryl ArrowsmithThomas SzyperskiAled EdwardsNESG MembersJohn Hunt

Funding:National Institutes of HealthBattelle Memorial InstituteDepartment of Energy Environmental Molecular Sciences LaboratoryMiami University

Lindsey Aaron Miki Theresa Shuisong KeyangRomick 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

ErikFeldman

undergraduates