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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.

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

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Janos zempleni ph d dept of nutrition and health sciences unl

Nebraska Center for the Prevention

of Obesity Diseases through

Dietary Molecules

Janos Zempleni, Ph.D.

Dept. of Nutrition and Health Sciences, UNL


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 obesity-related diseases, particularly cardiovascular disease and diabetes, and to devise intervention strategies for the prevention of these diseases.


Janos zempleni ph d dept of nutrition and health sciences unl

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)


Janos zempleni ph d dept of nutrition and health sciences unl

Significance (cont’d)

Age-adjusted percentage of adults aged ≥20 years with diagnosed diabetes, 2007

CDC


Janos zempleni ph d dept of nutrition and health sciences unl

Significance (cont’d)

Heart Disease hospitalization rates among U.S. Adults, CDC 2000 - 2006


Janos zempleni ph d dept of nutrition and health sciences unl

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.”


Janos zempleni ph d dept of nutrition and health sciences unl

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


Janos zempleni ph d dept of nutrition and health sciences unl

NPOD’s Map to Success

  • Study section members

  • Obesity COBREs

  • Website

  • Facebook


Janos zempleni ph d dept of nutrition and health sciences unl

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


Janos zempleni ph d dept of nutrition and health sciences unl

Specific Aim 1

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


Janos zempleni ph d dept of nutrition and health sciences unl

Administrative Core – the Edge

Administrative Core

Administrative Core


Janos zempleni ph d dept of nutrition and health sciences unl

Administrative Core

- Global Timeline -


Janos zempleni ph d dept of nutrition and health sciences unl

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.


Janos zempleni ph d dept of nutrition and health sciences unl

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


Janos zempleni ph d dept of nutrition and health sciences unl

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


Janos zempleni ph d dept of nutrition and health sciences unl

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)


Janos zempleni ph d dept of nutrition and health sciences unl

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


Janos zempleni ph d dept of nutrition and health sciences unl

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


Janos zempleni ph d dept of nutrition and health sciences unl

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


Janos zempleni ph d dept of nutrition and health sciences unl

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)


Janos zempleni ph d dept of nutrition and health sciences unl

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


Janos zempleni ph d dept of nutrition and health sciences unl

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


Janos zempleni ph d dept of nutrition and health sciences unl

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, andfatty acids are distinct between enterotypes

Collaborations of Fernando with Moreau, Wood,and Viswanathan?


Janos zempleni ph d dept of nutrition and health sciences unl

Mentoring Clusters

Cupp

Powers

Davis

Wilson

Cahoon

Desouza

Dussault

Harshman

Lee

Kachman

Benson

Zempleni

Lewis

Becker

Moriyama


Janos zempleni ph d dept of nutrition and health sciences unl

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


  • Janos zempleni ph d dept of nutrition and health sciences unl

    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


    Janos zempleni ph d dept of nutrition and health sciences unl

    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


    Janos zempleni ph d dept of nutrition and health sciences unl

    Specific Aim 3

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


    Janos zempleni ph d dept of nutrition and health sciences unl

    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


    Janos zempleni ph d dept of nutrition and health sciences unl

    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


    Janos zempleni ph d dept of nutrition and health sciences unl

    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


    Janos zempleni ph d dept of nutrition and health sciences unl

    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


    Janos zempleni ph d dept of nutrition and health sciences unl

    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


    Janos zempleni ph d dept of nutrition and health sciences unl

    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


    Janos zempleni ph d dept of nutrition and health sciences unl

    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.


    Janos zempleni ph d dept of nutrition and health sciences unl

    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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