TRUSTEES OF INDIANA UNIVERSITY
Hyperglycemia and insulin resistance are two major hallmarks of type 2 diabetes. Insulin resistance can cause dysregulation of hepatic gluconeogenesis that leads to the elevated blood glucose levels in diabetics.
Pyruvate dehydrogenase kinase 4 (PDK4) promotes gluconeogenesis through inhibition of glucose disposal at the level of the three-carbon intermediate metabolite -- pyruvate, and conservation of pyruvate as the
gluconeogenic substrate. Insulin suppresses the activity of PDK4 primarily through downregulation of its gene expression. Forkhead box O family of proteins (Foxos), which are known to be negatively regulated by insulin, have been shown to activate the PDK4 gene in vitro. However, it is not clear yet whether this is the case in vivo. This proposed study will use animal models to investigate whether and how Foxos are involved in the PDK4 gene regulation under normal and insulin resistant conditions. To accomplish this aim, mouse genetics and biochemical approaches will be used. The results from this study will advance our understanding of the regulatory mechanisms of PDK4 gene expression and provide in vivo data that may be helpful in targeting PDK4 for diabetes therapeutics.
| AWARD OVERVIEW |
| Award Number |
3R00DK077505-03S1 |
Funding Agency |
Department of Health and Human Services |
| Total Award Amount |
$71,000 |
Project Location - City |
INDIANAPOLIS |
| Award Date |
12/30/2009 |
Project Location - State |
IN |
| Project Status |
Completed |
Project Location - Zip |
46202-5122
|
| Jobs Reported |
0.00 |
Congressional District |
07 |
| Project Location - Country |
US |
|
|
Recipient Information
(Grants)
| Recipient Information (Grants) |
|
Recipient Name
|
TRUSTEES OF INDIANA UNIVERSITY |
| Recipient DUNS Number |
603007902
|
| Recipient Address |
620 UNION DR RM 618 |
| Recipient City |
INDIANAPOLIS |
| Recipient State |
Indiana |
| Recipient Zip |
46202-5130 |
| Recipient Congressional District |
07 |
| Recipient Country |
USA |
Required to Report Top 5
Highly Compensated Officials |
No |
Projects and Jobs Information
| Projects and Jobs Information |
| Project Title |
Role of pyruvate dehydrogenase kinases in glucose homeostasis |
| Project Status |
Completed |
| Final Project Report Submitted |
Yes |
| Project Activities Description |
Research and Development in the Physical, Engineering, and Life Sciences (except Biotechnology) |
| Quarterly Activities/Project Description |
The goal of this project is to understand the pathogenesis of hyperglycemia in diabetes. Since hepatic gluconeogenesis plays an important role in the development of hyperglycemia, we are investigating how dysregulation of pyruvate dehydrogenase kinases (PDKs)may lead to hyperglycemia. Recent findings from our study suggest that PDKs are regulated by Forkhead transcription factor Foxo1 and an NAD-dependent deacetylase Sirt1. With the support from this ARRA award, we were able to acquire the equipment (a high performance liquid chromatography (HPLC) analytical system and an ultracentrifuge rotor) to facilitate the research project. By using the HPLC system, we have successfully analyzed intracellular NAD levels in tissue culture cells and liver tissue. Determination of the concentration of this intermediate metabolite will help understand the regulatory mechanisms of NAD-dependent deacetylases including Sirt1. In order to conduct gain-of-function and loss-of-function analysis of the genes related to the project, we have taken advantage of adenovirus-mediated DNA transfer in vitro and in vivo. With the acquisition of the centrifuge rotor, we have purified several adenoviral preparations, including Foxo1 and Sirt1 overexpression and shRNA constructs. By using these reagents, we are currently elucidating the molecular mechanisms underlying the regulation of PDKs by Foxo1 and Sirt1. The project has advanced as planned. Recently, we have published the findings about feedback regulation of hepatic gluconeogenesis by Sirt1-Foxo1-Nr0b2 pathway. Ultimately, the knowledge gained from this project may provide a molecular foundation for developing therapeutics for diabetes. Work is complete and this is a final report |
| Jobs Created |
0.00 |
| Description of Jobs Created |
No jobs created/retained |
Purchaser Information
(Grants)
| Purchaser Information |
| Contracting Office ID |
Not Reported |
| Contracting Office Name |
Not Available |
| Contracting Office Region |
Not Available |
| TAS Major Program |
75-0883 |
| Award Information |
| Award Date |
12/30/2009 |
| Award Number |
3R00DK077505-03S1 |
| Order Number |
|
| Award Type |
Grants |
| Funding Agency ID |
75 |
| Funding Agency Name |
Department of Health and Human Services |
| Funding Office Name |
Not Available |
| Awarding Agency ID |
75 |
| Awarding Agency Name |
Department of Health and Human Services |
| Amount of Award |
$71,000 |
| Funds Invoiced/Received |
$71,000 |
| Expenditure Amount |
$71,000 |
| Infrastructure Expenditure Amount |
$0 |
| Infrastructure Purpose and Rationale |
Not Reported |
| Infrastructure Point of Contact Name |
Not Reported |
| Infrastructure Point of Contact Email |
Not Reported |
| Infrastructure Point of Contact Phone |
Not Reported |
| Infrastructure Point of Contact Address |
Not Reported |
| Infrastructure Point of Contact City |
Not Reported |
| Infrastructure Point of Contact State |
Not Reported |
| Infrastructure Point of Contact Zip |
Not Reported |
Product or Service Information
(Grants)
| Product or Service Information |
| Primary Activity Code |
541712 |
| Activity Description |
Research and Development in the Physical, Engineering, and Life Sciences (except Biotechnology) |
| Sub-Awards Information |
| Sub-awards to Organizations |
0 |
| Sub-award Amounts to Organizations |
$0 |
| Sub-Awards to Individuals |
0 |
| Sub-Award Amounts to Individuals |
$0 |
| Number of Sub-awards less than $25,000/award |
0 |
| Amount of Sub-awards less than $25,000/award |
$0 |
| Number of payments to vendors greater than $25,000 |
1 |
| Total Amount of payments to vendors greater than $25,000/award |
$53,987 |
| Number of payments to vendors less than $25,000/award |
6 |
| Total Amount of payments to vendors less than $25,000/award |
$17,047 |
AGILENT TECHNOLOGIES INC - Award Number 3R00DK077505-03S1 - AGILENT TECHNOLOGIES INC
| Award Number |
3R00DK077505-03S1 |
| Sub-Award Number |
N/A |
| Vendor DUNS Number |
Not reported |
| Vendor HQ Zip Code + 4 |
19808-0000 |
| Vendor Name |
AGILENT TECHNOLOGIES INC |
| Product and Service Description |
Analytical Laboratory Instrument Manufacturing |
| Payment Amount |
$53,987 |
| Location Information |
| Latitude, Longitude |
39º 46' 38",
-86º 10' 36" |
| Congressional District |
07 |
| Address 1 |
MS 4053, |
| Address 2 |
|
| City |
INDIANAPOLIS |
| County |
Marion |
| State |
IN |
| Zip |
46202-5122 |
|
|