UNIVERSITY OF MASSACHUSETTS
Project Description: The importance of innate immune cells in the pathophysiology of alcoholic liver injury is evident from animal models and human studies. Resident macrophages in the liver are activated by endotoxin in portal circulation to produce inflammatory cytokines. In addition to the pro-inflammatory cytokines, macrophages also produce chemokines that can contribute to alcoholic liver injury. Our preliminary studies show increased production of serum and liver tissue MCP-1 production after chronic alcohol feeding in mice. We also show that MCP-1 deficient mice exhibit significantly decreased liver injury after chronic alcohol feeding. Increased MCP-1 in the liver can promote monocyte/macrophage infiltration in the liver and contribute to inflammatory responses. Activation of monocyte/macrophages is pivotal to the development of alcoholic liver injury. We hypothesize that chronic alcohol exposure induces MCP-1 in the liver and its receptor, CCR2 on circulating monocyte/macrophages facilitating their recruitment to the liver. Altered MCP-1/CCR2 signaling could thus contribute to innate immune cell-mediated alcoholic liver injury. The objectives of the current proposal are to determine the role of MCP-1/CCR2 axis in alcohol-induced liver injury. Specifically, our focus will be to first perform a longitudinal analysis of MCP-1 expression in the liver and correlate these changes with alterations in resident and infiltrating macrophages in the liver after chronic alcohol feeding. Next, we will analyze the MCP-1 receptor, CCR2 on circulating monocytes after chronic alcohol feeding. We will also determine the effect of chronic alcohol on chemotaxis of CCR2-expressing monocyte/macrophages in an in vitro assay. Finally, using CCR2 knockout mice we will determine the pathophysiological significance of the MCP-1/CCR2 axis in alcoholinduced fatty liver injury. To achieve these objectives, the following specific aims are proposed: 1) Determine whether MCP-1 is required for alcohol-induced liver injury and intracellular mechanisms involved and 2) Investigate the effect of chronic alcohol on CCR2, a MCP-1 receptor, on circulating monocyte/macrophages its functional significance in alcohol-induced liver injury.
| AWARD OVERVIEW |
| Award Number |
1R21AA017545-01A1 |
Funding Agency |
Department of Health and Human Services |
| Total Award Amount |
$246,750 |
Project Location - City |
Worcester |
| Award Date |
09/07/2010 |
Project Location - State |
MA |
| Project Status |
Completed |
Project Location - Zip |
01655-0002
|
| Jobs Reported |
0.10 |
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 |
ARRA: Regulation of MCP-1 and chemokine receptor 2 (CCR2) in alcoholic liver |
| Project Status |
Completed |
| Final Project Report Submitted |
Yes |
| Project Activities Description |
Medical Research, General/Other |
| Quarterly Activities/Project Description |
The Specific Aims of the proposal remain unchanged. In this quarter we focused on expts in specific aim #2.Investigate the effect of chronic alcohol on CCR2, a MCP-1 receptor, in alcohol-induced liver injury. Our earlier studies showed that CCR2 deficient (CCR2KO) mice administered the Leiber-deCarli alcohol diet for 6 weeks exhibit slightly increased serum ALT, a marker of liver injury, compared to WT counterparts, indicating that absence of CCR2 did not protect from alcoholic liver injury. Furthermore, absence of CCR2 resulted in increased liver triglycerides confirmed by compared to pair-fed controls similar to wild-type mice. Previous studies showed that MCP1 deficiency in alcohol-fed mice regulates macrophage activation, as analyzed by mRNA expression of CD68 a macrophage activation marker. Recent mRNA analysis in alcohol fed CCR2 knockout mice showed significantly decreased CD68, CD11b and F4/80 expression compared to alcohol fed wild type controls suggesting reduced macrophage infiltration due to CCR2 deficiency. Furthermore, CCR2 deficiency in alcohol fed mice resulted in decreased CD11b+Ly6C+ inflammatory monocytes compared to wild-type controls indicating that inflammatory macrophages recruited to the liver during alcohol feeding are critical in tissue repair. These results suggest that CCR2 may contribute to protective rather than pathological mechanisms during alcoholic liver injury. Furthermore, effects of MCP-1 on alcohol induced fatty liver are independent of CCR2. The final expenses will be invoiced in the next couple weeks |
| Jobs Created |
0.10 |
| Description of Jobs Created |
Assoc Professor |
Purchaser Information
(Grants)
| Purchaser Information |
| Contracting Office ID |
Not Reported |
| Contracting Office Name |
Not Available |
| Contracting Office Region |
Not Available |
| TAS Major Program |
75-0909 |
| Award Information |
| Award Date |
09/07/2010 |
| Award Number |
1R21AA017545-01A1 |
| 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 |
$246,750 |
| Funds Invoiced/Received |
$246,649 |
| Expenditure Amount |
$246,750 |
| 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 |
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 |
0 |
| Total Amount of payments to vendors greater than $25,000/award |
$0 |
| Number of payments to vendors less than $25,000/award |
95 |
| Total Amount of payments to vendors less than $25,000/award |
$33,364 |
| 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 |
|
 |