Janos Zempleni , Ph.D. Dept. of Nutrition and Health Sciences, UNL

1. Nebraska Center for the Prevention of Obesity Diseases through Dietary Molecules Janos Zempleni, Ph.D. Dept. of Nutrition and Health Sciences, UNL

3. NPOD Mission It is the mission of NPOD to discover mechanisms through which dietary molecules prevent obesity-related diseases, particularly cardiovascular disease and diabetes, and to devise intervention strategies for the prevention of these diseases.

4. Significance Obesity among U.S. Adults, CDC 2010 No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30% (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

5. Significance (cont’d) Age-adjusted percentage of adults aged ≥20 years with diagnosed diabetes, 2007 CDC

6. Significance (cont’d) Heart Disease hospitalization rates among U.S. Adults, CDC 2000 - 2006

7. NIH’s Response to this Crisis NIH Strategic Plan for Obesity Research, 2011 • Discover the biological mechanisms leading to obesity and related diseases • Train a multidisciplinary scientific workforce • Devise efficient, effective, and fast approaches to translation in medical • and community settings 2011 NIH program announcements NIH PA-11-165:“Heart failuredemands more effectivelow-cost management approaches […]dietary factors and nutritionaldeficiencies areknown to cause heart failure in humans as well.” NIH PA-11-170:“Type 2 diabetes studies should assess the mechanisms of developmental programming, epigenetic changes, genetic background, nutrition, the microbiome, and inflammation that lead to diabetes.”

8. NPOD is Unique Centers of Biomedical Research Excellence on • Policies that Cause Health Disparities in Alaska Natives • Fetal Programming • Molecular Basis of Human Disease • Cardiovascular Biology

9. NPOD’s Map to Success • Study section members • Obesity COBREs • Website • Facebook

10. Nebraska Gateway for Nutrigenomics • Founded in 2008 • Retreats, seminar series • Collaborations across 17 units • Joint grant applications, including T32 • Junior investigator pilot grant program • Strategic priority for NHS, CEHS, IANR/ARD, UNL Mid-term goal: advance to Center status

11. Specific Aim 1 Establish an NPOD administrative core of personnel and programs that support and enhance the Center’s research.

12. Administrative Core – the Edge Administrative Core Administrative Core

13. Administrative Core - Global Timeline -

14. Specific Aim 2 Develop a critical mass of faculty through the support of five thematically linked primary research projects, a strong mentoring program for junior investigators, and through support of two essential research core facilities and a pilot grant program.

15. Center Projects Regis Moreau Redox signaling, selenoproteins Dmitri Fomenko Lipoic acid signaling, hyperlipidemia Dietary Molecules ω-3 fatty acids, pro-inflammatory processes, hyperlipidemia Cardiovascular disease and diabetes Saraswathi Viswanathan Gut microbe signaling Samodha Fernando Fetal programming, pro-inflammatory processes Jennifer Wood Tenure track appointments Identified through an open competition

16. Anti-lipemic Signaling Mechanisms of R-α-Lipoic Acid (LA) Regis Moreau, Ph.D.Assistant ProfessorDepartment of Nutrition and Health SciencesUniversity of Nebraska-Lincoln LA

17. Novel Molecular Targets of LA LA TSC1/2 FGF21 LA X6 β-Klotho mTORC1 Rheb FGFR1 SREBP1c Tf ChREBP Tf β-oxidationgenes X5 Lipogenic genesACC, FAS, GPAT1, DGAT2 Fgf21 Liver Liver Muscle Fibroblast growth factor-21 (FGF21) mediates the lipolytic properties of LA. (Tf = Transcription factor) LA downregulates SREBP1c-mediated transcription of lipogenic genes through inactivation mTORC1 (mammalian target of rapamycin complex 1)

18. Experimental Models • Fgfr1f/f/Cremice lacking fibroblast growth factor-21 (FGF21) receptor • Tsc1f/f/Cre mice constitutively expressing mammalian target of rapamycin complex 1 (mTORC1) Cre/ESR Fgfr1 +Tamoxifen Gt(ROSA)26Sor Cre ESR loxP loxP Fgfr1 KO Cre/ESR Tsc1 +Tamoxifen Gt(ROSA)26Sor Cre ESR loxP loxP Tsc1 KO

19. Innovation • Shift from the current paradigm that LA acts as an antioxidant • Novel lipid-lowering mechanisms of LA • Stimulation of lipid clearance • Downregulation of triglyceride synthesis Outcome • Safe and economical alternative to current lipid-lowering therapies • Mechanism-based rationale for clinical trials with LA

20. Redox Signaling and SelenoproteinsAlter Diabetes Risk Dmitri Fomenko, Ph.D.Assistant ProfessorDepartment of Biochemistry and Redox Biology CenterUniversity of Nebraska-Lincoln Redoxstress, impaired H2O2 signaling Type I and II diabetes ER stress

21. Signals of the Gut Microbiome that Ameliorate the Obesity Phenotype Samodha Fernando, Ph.D.Assistant ProfessorDepartment of Animal ScienceUniversity of Nebraska-Lincoln Kinross et al.Genome Medicine 2011 3:14   (www.genome.gov)

22. Placental Function Organ Development Fetal Programming of Cardiovascular Disease and Diabetes Jennifer Wood, Ph.D.Assistant ProfessorDepartment of Animal Science University of Nebraska-Lincoln Uterine Environment Oviduct/ In vitro Environment Cardiovascular Disease Obesity/Diabetes

23. Role of PXR Signaling in Mediating the Cardioprotective Effects of -3 Fatty Acids SaraswathiViswanathan, Ph.D.Assistant ProfessorDepartment of Internal Medicine/DEMUniversity of Nebraska Medical Center-Omaha Lipid-lowering Effects Cardioprotective Effects -3 Fatty Acids (EPA & DHA) Anti-inflammatory Effects

24. Synergies Among Center Projects Example 1: Lipoic acid is an ω-substituted fatty acid Are Moreau/Viswanathan looking at the same mechanism? Example 2: The intake of lipoate, methyl donors, and fatty acids are distinct between enterotypes Collaborations of Fernando with Moreau, Wood, and Viswanathan?

25. Mentoring Clusters Cupp Powers Davis Wilson Cahoon Desouza Dussault Harshman Lee Kachman Benson Zempleni Lewis Becker Moriyama

26. Pilot Grant Programs • Pre-tenure faculty: • $50k/year for 2 years • Objective: Identify and prepare faculty for project leader slots • Four candidates have been identified (3 UNL, 1 UNMC) • Multidisciplinary grants: • $100k/year for 2 years • Objective: Stimulate multidisciplinary research; sustainability • PI is a Center member, others may come from any IDeA state • T32 • Director’s responsibility • Objective: Keep members involved; recruit high-quality students • and postdocs; faculty recruiting tool

27. Epigenetics Core • Comprehensive service, including study design • and data analysis • Director, co-director, and staff have been identified • Space has been identified • Remodeling is within the NIH $300k allowance • Useful to all Center members

28. Computational and Data Sharing Core • Existing center with offices in Lincoln and Omaha • Director and NPOD Liaison have been identified • Services will be tailored to meet NPOD needs • Free accounts to all Center members • Accounts available to external users • Networked with Epigenetics core • Pilot-tested by NGN faculty • Key to data and file sharing with collaborators, among • mentoring cluster members, and with public

29. Specific Aim 3 Increase research capacity through targeted recruitment of five researchers in areas key to Center success.

30. Hire 1 • Molecular Genetics (NHS, UNL) • Search is nearing completion • Number 1 ranked candidate has an exceptionally strong research program in overeating and ER stress • Good opportunities for collaboration with the Redox center and with Dmitri Fomenko

31. Hire 2 • Pharmacology and Biotransformation of Dietary Molecules (UNL) • Dietary molecules are subject to biotransformation • Task force group of faculty from NHS and FST • Good opportunities for collaboration with any Center member

32. Hire 3 • Fetal Programming and Adult Disease (UNL) • Clusters of strength in various departments at UNL • Focus on ncRNA/miRNA in mammalian systems • NIH priority area • Tenure home in UNL’s Departments of Animal Science, Biological Systems Engineering, Biochemistry, Nutrition and Health Sciences, or split appointment

33. Hire 4 • Epidemiology and Genetics with Expertise in Genome-wide Association Studies (UNL) • Translation into human research • Access to human databases • Project leaders may test their hypothesis in human populations • Strategic priority hire for NHS but also a good fit for • Statistics

34. Hire 5 • Adipocyte Differentiation (UNL) • Dietary molecules that regulate the differentiation of stem cells into adipocytes • Novel concept (NIH RFA-ES-11-010) • Cluster of investigators at UNL (Pannier, Schlegel, Wang, Zempleni) • Tenure home in Animal Science, Biological Systems Engineering, Biochemistry, Nutrition and Health Sciences, or split appointment

35. UNMC • NPOD contacts Drs. Davis, Desouza, and Lewis • UNMC Dept. Heads and Div. Chiefs (Batra, Kabanov, Zucker) • Drs. Viswanathan (project leader) and Mott (pilot grant) • Coordinating Committee

36. Specific Aim 4 Graduate from IDeA program funding as a self-sustainable center of research excellence through the development of program projects and collaborative research grants.

37. Strategies • P01 grants (stimulated by pilot grant program) • MPI R01 grants (stimulated by pilot grant program) • T32 training grants • Fees for core facilities • Donors? • NGN retreat: Bayer Health, Mead Johnson, Campbell’s Soup, Kemin