NGN - Office of Research & Economic Development

Report
Nebraska Center for the Prevention
of Obesity Diseases through
Dietary Molecules
Janos Zempleni, Ph.D.
Dept. of Nutrition and Health Sciences, UNL
NPOD Mission
It is the mission of NPOD to discover mechanisms
through which dietary molecules prevent obesityrelated diseases, particularly cardiovascular disease
and diabetes, and to devise intervention strategies
for the prevention of these diseases.
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)
Significance (cont’d)
Age-adjusted percentage of adults aged ≥20 years with diagnosed diabetes,
2007
CDC
Significance (cont’d)
Heart Disease hospitalization rates among U.S. Adults, CDC 2000 - 2006
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 failure demands more effective low-cost management
approaches […] dietary factors and nutritional deficiencies are known 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.”
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
NPOD’s Map to Success
• Website
• Facebook
• Study section members
• Obesity COBREs
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
Core – the Edge
Administrative
Core
Administrative Core
- Global Timeline Activity
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
Year 1
Year 2
Year 3
Year 4
Year 5
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
Regis Moreau
Lipoic acid signaling,
hyperlipidemia
Redox signaling,
selenoproteins
Dmitri Fomenko
DIETARY
MOLECULES
Saraswathi
Viswanathan
ω-3 fatty acids,
pro-inflammatory
processes,
hyperlipidemia
Cardiovascular
disease and
diabetes
Fetal programming,
pro-inflammatory
processes
Gut microbe
signaling
Samodha Fernando
Jennifer Wood
Tenure track appointments
Identified through an open competition
Anti-lipemic Signaling Mechanisms of
R-α-Lipoic Acid (LA)
Regis Moreau, Ph.D.
Assistant Professor
Department of Nutrition and Health Sciences
University of Nebraska-Lincoln
LA
Novel Molecular Targets of LA
LA
LA
FGFR1
X6
β-Klotho
FGF21
Tf
mTORC1
TSC1/2
Rheb
SREBP1c
ChREBP
Tf
X5
Fgf21
Liver
β-oxidation
genes
Muscle
Lipogenic genes
ACC, FAS, GPAT1, DGAT2
Liver
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)
Experimental Models
•
Fgfr1f/f/Cre mice lacking fibroblast growth factor-21 (FGF21) receptor
Cre/
ESR
Gt(ROSA)26Sor
Cre
ESR
+
Tamoxifen
Fgfr1
loxP
loxP
Fgfr1 KO
•
Tsc1f/f/Cre mice constitutively expressing mammalian target of rapamycin
complex 1 (mTORC1)
Cre/
ESR
Gt(ROSA)26Sor
Cre
ESR
+
Tamoxifen
Tsc1
loxP
loxP
Tsc1 KO
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 Professor
Department of Biochemistry and Redox Biology Center
University 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 Professor
Department of Animal Science
University 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 Professor
Department of Animal Science
University of Nebraska-Lincoln
Oviduct/ In vitro
Environment
Uterine
Environment
Placental Function
Organ Development
Cardiovascular Disease
Obesity/Diabetes
Role of PXR Signaling in Mediating the
Cardioprotective Effects of -3 Fatty Acids
Saraswathi Viswanathan, Ph.D.
Assistant Professor
Department of Internal Medicine/DEM
University of Nebraska Medical Center-Omaha
Lipid-lowering
Effects
Cardioprotective
Effects
-3 Fatty Acids
(EPA & DHA)
Anti-inflammatory
Effects
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?
Cupp
Becker
Desouza
Dussault
Harshman
Davis
Lee
Cahoon
Wilson
Moriyama
Zempleni
Powers
Benson
Kachman
Mentoring Clusters
Lewis
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 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
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 selfsustainable 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

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