UNIVERSITY OF MASSACHUSETTS
Obesity and health complications related to obesity, including diabetes, impact a significant proportion of the population in the United States, and projections indicate that the number of obese and overweight individuals will continue to rise in the future. The costs of health care due to the physical and psycho-social problems caused by obesity and related complications, coupled with the associated loss of productivity, is staggering. Improving strategies to induce lifestyle changes among the obese and overweight population is a necessary strategy toward alleviating this problem, but this approach should be complemented by continued basic research addressing the physiological processes regulating weight gain and adipose formation. While the regulation of adipogenesis by adipogenic transcription factors has been extensively examined, epigenetic regulators of adipogenesis have not received as much attention. We provide evidence that ATP-dependent chromatin remodeling enzymes and arginine methyltransferases are critical regulators of adipose formation and propose to investigate the mechanisms of action of these enzymes in adipose formation and function in culture and in vivo. Specifically, we will investigate the functional contributions of the histone arginine methyltransferases Prmt5 and Prmt4 in regulating adipogenic gene expression. Additional effort will be placed on investigating the dynamics of histone arginine methylation during adipose formation and function by examining arginine demethylase enzymes. Modulation of epigenetic regulators of gene expression has already proven clinically useful: understanding how such regulators function potentially may lead to strategies that modulate adipogenesis in a manner that is useful for the treatment of obesity and obesity related disease.
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| AWARD OVERVIEW |
| Award Number |
1R01DK084278-01 |
Funding Agency |
Department of Health and Human Services |
| Total Award Amount |
$746,038 |
Project Location - City |
Worcester |
| Award Date |
09/18/2009 |
Project Location - State |
MA |
| Project Status |
Completed |
Project Location - Zip |
01655-0002
|
| Jobs Reported |
0.00 |
Congressional District |
03 |
| Project Location - Country |
US |
|
|
Recipient Information
(Grants)
| Recipient Information (Grants) |
|
Recipient Name
|
UNIVERSITY OF MASSACHUSETTS |
| Recipient DUNS Number |
603847393
|
| Recipient Address |
55 LAKE AVE N |
| Recipient City |
WORCESTER |
| Recipient State |
Massachusetts |
| Recipient Zip |
01655-0002 |
| Recipient Congressional District |
03 |
| Recipient Country |
USA |
Required to Report Top 5
Highly Compensated Officials |
No |
Projects and Jobs Information
| Projects and Jobs Information |
| Project Title |
Epigenetic Control of Adipogenesis |
| Project Status |
Completed |
| Final Project Report Submitted |
Yes |
| Project Activities Description |
Medical Research, General/Other |
| Quarterly Activities/Project Description |
Summary as of 9-24-12: As a follow-up to our work describing a role for the protein arginine methyltransferase PRMT5 in regulating PPAR?2 and PPAR?2 target gene expression in differentiating adipocyte cells (LeBlanc et al, Mol. Endocrinol., 26:583, 2012), we are examining intra-chromosomal interactions between the PPAR?2 promoter and regions upstream and downstream, with a particular interest in a putative enhancer region that undergoes transitory changes in histone acetylation along with an increase in DNAse I hypersensitivity during adipogenesis. Differentiation-dependent and ?independent changes have been observed, and a time course experiment indicates that these changes occur well in advance of PPAR?2 gene expression. Continued characterization of the conformational changes occurring at this locus is underway. Initial evidence suggest the involvement of PRMT5, and we are attempting to understand the mechanism. We have identified PRMT5-specific arginine demethylases (RDMs) capable of erasing PRMT5-induced epigenetic marks. Our results indicate that several RDMs are required for adipogenesis in culture. Analysis of the expression of different adipogenic genes indicates that the requirement for one of the RDMs is early in the adipogenic differentiation process. Recent advances suggest that regulatory proteins expressed early in differentiation are being regulated at a post-transcriptional level. Proteosome- and lysosome-mediated degradation do not appear to be involved. mRNA export pathways are under further investigation to better understand the role played by these RDMs in adipogenesis are underway. In addition, we have determined individual knockdown of two of the demethylases alters cell growth properties and may play a role in cell cycle progression. Cell cycle analysis in asynchronous and in synchronized cells suggest that the two RDMs are affecting cell cycle differently. The final expenses will be invoiced in the next couple weeks |
| Jobs Created |
0.00 |
| Description of Jobs Created |
No employees were funded on the project during the current quarter. |
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 |
09/18/2009 |
| Award Number |
1R01DK084278-01 |
| 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 |
$746,038 |
| Funds Invoiced/Received |
$743,747 |
| Expenditure Amount |
$743,747 |
| 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 |
H01 |
| Activity Description |
Medical Research, General/Other |
| Sub-Awards Information |
| Sub-awards to Organizations |
1 |
| Sub-award Amounts to Organizations |
$270,000 |
| 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 |
0 |
| Total Amount of payments to vendors greater than $25,000/award |
$0 |
| Number of payments to vendors less than $25,000/award |
104 |
| Total Amount of payments to vendors less than $25,000/award |
$28,311 |
Sub-award 0006113883 - OHIO STATE UNIVERSITY RESEARCH FOUNDATION
| Sub-Award Amount |
$270,000 |
| Sub-Award Date |
10/26/2009 |
| Sub-Awards Disbursed |
$266,625.90 |
| Project Location - City |
COLUMBUS |
| Project Location - State |
OH |
| Project Location - Zip Code |
43210-1063 |
| Project Location - Congressional District |
15 |
| Sub-Recipient DUNS Number |
071650709
|
| Sub-Recipient Address |
1960 KENNY RD |
| Sub-Recipient City |
COLUMBUS |
| Sub-Recipient State |
Ohio |
| Sub-Recipient Zip Code |
43210-1016 |
| Sub-Recipient Congressional District |
15 |
Required To Report Top 5
Highly Compensated Officials |
No |
| Location Information |
| Latitude, Longitude |
42º 16' 39",
-71º 45' 33" |
| Congressional District |
03 |
| Address 1 |
55 Lake Avenue North |
| Address 2 |
|
| City |
Worcester |
| County |
Worcester |
| State |
MA |
| Zip |
01655-0002 |
|
 |