janos zempleni , ph.d. dept. of nutrition and health sciences, unl
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Nebraska Center for the Prevention of Obesity Diseases through Dietary Molecules. Janos Zempleni , Ph.D. Dept. of Nutrition and Health Sciences, UNL. NPOD Mission. - PowerPoint PPT PresentationTRANSCRIPT
Janos Zempleni, Ph.D.Dept. of Nutrition and Health Sciences, UNL
Nebraska Center for the Preventionof Obesity Diseases through
Dietary Molecules
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.
(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)
No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%
SignificanceObesity among U.S. Adults, CDC 2010
Age-adjusted percentage of adults aged ≥20 years with diagnosed diabetes, 2007
Significance (cont’d)
CDC
Significance (cont’d)Heart Disease hospitalization rates among U.S. Adults, CDC 2000 - 2006
NIH’s Response to this Crisis
NIH PA-11-165: “Heart failure demands more effective low-cost managementapproaches […] dietary factors and nutritional deficiencies are known tocause heart failure in humans as well.”
2011 NIH program announcements
NIH PA-11-170: “Type 2 diabetes studies should assess the mechanisms ofdevelopmental programming, epigenetic changes, genetic background,nutrition, the microbiome, and inflammation that lead to diabetes.”
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
NPOD is Unique
• Policies that Cause Health Disparities in Alaska Natives
• Fetal Programming• Molecular Basis of Human Disease• Cardiovascular Biology
Centers of Biomedical Research Excellence on
NPOD’s Map to Success
• Study section members• Obesity COBREs• Website
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
Specific Aim 1
Establish an NPOD administrative core of personnel and programs that support and enhance the
Center’s research.
Administrative CoreAdministrative Core – the EdgeAdministrative Core
Administrative Core- Global Timeline -
Activity Year 1 Year 2 Year 3 Year 4 Year 5
Establish Administrative Core, including hiring a 0.5 FTE office assistant to assist the center manager
“Kick-Off” meeting
Activate user accounts for the Computational and Data Sharing Core; open Core for use
Research project funding (Cohort 1)
Renovate and open Epigenetics Core for use
Seminar series
March and September retreats
Complete Hire #1 (molecular geneticist)
Award one to two pilot grants (pre-tenure category)
Submit NIH T32 training grant application
Complete Hires #2 (pharmacology and biotransformation) and #3 (fetal programming and adult disease)
Award two pilot grants (pre-tenure category)
Award one pilot grant (multidisciplinary category)
Complete Hire #4 (epidemiology and genetics)
Award two pilot grants (pre-tenure category)
Cohort 1 project leaders graduates to R01 status
Research project funding (Cohort 2)
Complete Hire #5 (adipocyte differentiation)
Award one to two pilot grants (pre-tenure category)
Award one pilot grant (multidisciplinary category)
Develop/submit NIH P01 Applications
Develop/submit Phase II COBRE Application
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.
Center Projects
Identified through an open competition
SaraswathiViswanathan
Dmitri Fomenko
Samodha Fernando
Jennifer Wood
Regis Moreau
ω-3 fatty acids,pro-inflammatory processes,hyperlipidemia
Redox signaling,selenoproteins
Gut microbesignaling
Fetal programming,pro-inflammatory processes
Lipoic acid signaling,hyperlipidemia
Cardiovasculardisease and
diabetes
DIETARYMOLECULES
Tenure track appointments
Anti-lipemic Signaling Mechanisms ofR-α-Lipoic Acid (LA)
LA
Regis Moreau, Ph.D.
Assistant ProfessorDepartment of Nutrition and Health SciencesUniversity of Nebraska-Lincoln
Novel Molecular Targets of LA
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)
β-oxidationgenes
Tf
FGFR
1 β-K
loth
o
Fgf21
Tf
X5
FGF21LA
Liver Muscle
X6
SREBP1c
LA
ChREBP
Lipogenic genesACC, FAS, GPAT1, DGAT2
mTORC1 Rheb
TSC1/2
Liver
Experimental Models
• Fgfr1f/f/Cre mice lacking fibroblast growth factor-21 (FGF21) receptor
• Tsc1f/f/Cre mice constitutively expressing mammalian target of rapamycin complex 1 (mTORC1)
Gt(ROSA)26Sor Cre ESRTsc1
loxPloxP
Cre/ESR
+Tamoxifen
Tsc1 KO
loxP
Fgfr1 KO
Fgfr1
loxPGt(ROSA)26Sor Cre ESR
Cre/ESR
+Tamoxifen
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
Redox Signaling and Selenoproteins Alter Diabetes Risk
Dmitri Fomenko, Ph.D.
Assistant ProfessorDepartment of Biochemistry and Redox Biology CenterUniversity of Nebraska-Lincoln
Redox stress, impaired H2O2
signaling
ER stress
Type I and II diabetes
Signals of the Gut Microbiome that Ameliorate the Obesity Phenotype
Samodha Fernando, Ph.D.
Assistant ProfessorDepartment of Animal ScienceUniversity of Nebraska-Lincoln
(www.genome.gov) Kinross et al. Genome Medicine 2011 3:14
Fetal Programming of Cardiovascular Disease and Diabetes
Jennifer Wood, Ph.D.
Assistant ProfessorDepartment of Animal ScienceUniversity of Nebraska-Lincoln
Oviduct/ In vitro Environment
Uterine Environment
Placental FunctionOrgan Development
Cardiovascular DiseaseObesity/Diabetes
Role of PXR Signaling in Mediating the Cardioprotective Effects of -3 Fatty Acids
Saraswathi Viswanathan, Ph.D.
Assistant ProfessorDepartment of Internal Medicine/DEMUniversity of Nebraska Medical Center-Omaha
Anti-inflammatory Effects
Lipid-lowering Effects
-3 Fatty Acids(EPA & DHA)
CardioprotectiveEffects
Synergies Among Center Projects
Example 1: Lipoic acid is an ω-substituted fatty acidAre Moreau/Viswanathan looking at the samemechanism?
Example 2: The intake of lipoate, methyl donors, andfatty acids are distinct between enterotypesCollaborations of Fernando with Moreau, Wood,
and Viswanathan?
Mentoring Clusters
Moriyama
Benson
Kac
hman
Davis
PowersC
upp
Lewis
DussaultD
esou
za
Becker
LeeH
arsh
man
Zempleni
CahoonW
ilson
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
Epigenetics Core
• Comprehensive service, including study designand 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
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
Specific Aim 3
Increase research capacity through targeted recruitment of five researchers in areas key to
Center success.
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
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
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
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
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
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
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.
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