WORCESTER POLYTECHNIC INSTITUTE
Tuberculosis is a leading health problem worldwide. Mycobacterium tuberculosis virulence is based on its capability to reside inside macrophages. At the center of its pathogenic strategy is the handling of involved heavy metals (Cu+, Zn2+, Fe2+, Mn2+, etc.), protons and perhaps alkali metals such as K+ and Mg2+. M. tuberculosis genome reveals the presence of numerous heavy metal ATPases of unknown substrate. We hypothesize that the pathophysiological role of these transporters is primarily determined by their substrate specificity. Metal specificities of a subset of these P-type ATPases will be determined by expressing these in E. coli, examining bacterial gain of function, and measuring the enzymatic and transport activity. Previous studies suggest that CtpC and CtpD are particularly relevant for in vivo (macrophage) M. tuberculosis growth. Testing this, M. tuberculosis mutants will be constructed along with strains overexpressing these proteins. Their virulence (in mice and cultured macrophages) and fitness to growth in various media will be assessed. The impact of mutating and overexpressing these proteins on M. tuberculosis metal homeostasis and its ability to respond to the host redox attack will be determined. Results form these studies will provide an initial appreciation of these proteins importance and enable the generation meaningful testable hypothesis on the biological function of these transporters.
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| AWARD OVERVIEW |
| Award Number |
1R21AI082484-01 |
Funding Agency |
Department of Health and Human Services |
| Total Award Amount |
$439,943 |
Project Location - City |
Worcester |
| Award Date |
07/20/2009 |
Project Location - State |
MA |
| Project Status |
Completed |
Project Location - Zip |
01609-2280
|
| Jobs Reported |
0.00 |
Congressional District |
03 |
| Project Location - Country |
US |
|
|
Recipient Information
(Grants)
| Recipient Information (Grants) |
|
Recipient Name
|
WORCESTER POLYTECHNIC INSTITUTE |
| Recipient DUNS Number |
041508581
|
| Recipient Address |
100 INSTITUTE RD |
| Recipient City |
WORCESTER |
| Recipient State |
Massachusetts |
| Recipient Zip |
01609-2280 |
| 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 |
Mycobacterium Tuberculosis Metal Transport P-Type AT Pases |
| Project Status |
Completed |
| Final Project Report Submitted |
Yes |
| Project Activities Description |
Science & Technology, General/Other |
| Quarterly Activities/Project Description |
Using Mycobacterium tuberculosis and M. smegmatis mutants, the response and role of target molecules (CtpC and CtpD ATPases) to various stress conditions were tested. It was observed that one of the targeted transporters (CtpC) is necessary for resistance to Cu(II), Co(II) and reducing agents. CtpC was cloned, expressed, and its enzymatic activity has been determined, as well as its in vivo upregulation in the presence of Cu(II) and reducing agents. Mn(II) Cu(II) and Co(II) binding to this ATPase was also established. The biochemical characterization of these enzymes has been completed. Experiments testing the virulence of M. tuberculosis mutants lacking the target genes were concluded. The role of CtpC in the assembly of superoxidese dismutase, a protein that is critical for virulence, has been established. This is an important breakthrough on our understanding of how metallo proteins are assembled in M. tuberculosis. |
| Jobs Created |
0.00 |
| Description of Jobs Created |
There were no jobs created for this quarter. |
Purchaser Information
(Grants)
| Purchaser Information |
| Contracting Office ID |
Not Reported |
| Contracting Office Name |
Not Available |
| Contracting Office Region |
Not Available |
| TAS Major Program |
75-0900 |
| Award Information |
| Award Date |
07/20/2009 |
| Award Number |
1R21AI082484-01 |
| 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 |
$439,943 |
| Funds Invoiced/Received |
$439,943 |
| Expenditure Amount |
$439,718 |
| Infrastructure Expenditure Amount |
$439,718 |
| 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 |
U01 |
| Activity Description |
Science & Technology, 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 |
186 |
| Total Amount of payments to vendors less than $25,000/award |
$53,238 |
| Location Information |
| Latitude, Longitude |
42º 16' 21",
-71º 48' 27" |
| Congressional District |
03 |
| Address 1 |
100 Institute Rd |
| Address 2 |
|
| City |
Worcester |
| County |
Worcester |
| State |
MA |
| Zip |
01609-2280 |
|
 |