HHS Recovery Act Recipient Reporting Readiness Tool

Step 4. Review and Copy the Grant Awards Data

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Prime Recipient Report

Award Detail for: MODELING AND RESCUE OF DBA IN THE MOUSE
Recipient Name:WASHINGTON UNIVERSITY
DUNS Number: 068552207
CAMPUS BOX 1034
SAINT LOUIS, MO 63112

Reporting Information

Award Type*: Grant

Award Number*: RC1DK086230-1-001

Final Report*: Recipient responsible for this data

Award Recipient Information

Recipient DUNS Number*: 068552207

Recipient Account Number: Recipient responsible for this data

Recipient Congressional District*: 1

Award Information

Funding Agency Code*: 7529

Awarding Agency Code*:7529

Award Date*: 02-22-2011

Amount of Award*: $- 80,951

Program Source (TAS)*: 750883

CFDA Number*: 93.701

Sub Account Number for Program Source (TAS)*: Recipient responsible for this data

Total Number of Sub Awards to Individuals*: Recipient responsible for this data

Total Amount of Sub Awards to Individuals*: Recipient responsible for this data

Total Number of Payments to Vendors less than $25,000/award*: Recipient responsible for this data

Total Amount of Payments to Vendors less than $25,000/award*: Recipient responsible for this data

Total Number of Sub Awards less than $25,000/award*: Recipient responsible for this data

Total Amount of Sub Awards less than $25,000/award*: Recipient responsible for this data

Award Description* DESCRIPTION (provided by applicant): This application addresses the broad Challenge Area (15) "Translational Sciences and specifically the challenge topic 15-DK-106 : Translating basic hematology concepts". Diamond Blackfan anemia is a rare bone marrow failure syndrome characterized by red cell aplasia, congenital abnormalities and a predisposition to cancer. Heterozygous mutations in ribosomal protein genes have been found in approximately 50% of DBA patients. As all patients identified to date are heterozygous for these mutations, haploinsufficiency has been suggested as the mechanism underlying the pathogenesis of DBA. However, the relationship between ribosomal protein deficiency and defective erythropoiesis is not known. Work from several groups has demonstrated an intriguing connection between ribosomal proteins, specifically RPL5 and RPL11, and the regulation of p53. In human cell lines with a wild type p53 response, depletion of ribosomal proteins causes cell cycle arrest and induction of p53 and p21. Interestingly, this response and cell cycle arrest can be abrogated by simultaneous depletion of either p53 or RPL11. From this, we hypothesize that DBA is caused by disrupted ribosome biogenesis causing an imbalance of ribosomal proteins that, by inhibiting MDM2, causes an activation of the p53 pathway that is detrimental to the maturing red cells. We further hypothesize that modulation of this downstream pathway may correct the erythroid defect. One factor that has greatly limited investigations into the pathogenesis of DBA is the absence of a model that recapitulates the hematopoietic defects seen in DBA patients. Therefore we have generated a mouse model that closely mimics DBA hematopoiesis. We now propose to test our hypotheses and further characterize the block in red cell differentiation in these mice. We will rescue erythropoiesis in vitro and subsequently in vivo by manipulating the levels of key components shown to link defective ribosome biogenesis to the activation of p53. These experiments will provide important new insights into how ribosome biogenesis regulates cell proliferation in vivo. Moreover these experiments approach the major puzzle about DBA pathogenesis, namely how does haploinsufficiency of a housekeeping gene cause a defect in one specific cell type to produce red cell aplasia in DBA? Additionally, an animal model mimicking the hematopoiesis of patients with DBA which can be rescued in vitro and in vivo will be invaluable for developing and testing novel drugs that may eventually improve the treatment of DBA and possibly other diseases caused by ribosomal defects. PUBLIC HEALTH RELEVANCE: Diamond Blackfan anemia is a genetic blood disorder that manifests with a severe anemia in childhood. The disease is caused by failure to make red blood cells due to problems in the protein synthesis machinery. To study the disease mechanism in more detail we propose to generate a mouse model that has the same genetic defect and the same problems in red blood cell production as patients with DBA. We plan to investigate the defect in red blood cell production in these mice in great detail and test whether interference with the pathway that causes the problem will rescue red blood cell production. These studies may lead to greater understanding of DBA and of ways we might treat this disease.

Project Information

Project Name or Project/Program Title*: MODELING AND RESCUE OF DBA IN THE MOUSE

Project Status*: Recipient responsible for this data

Total Federal Amount of ARRA Funds Received/Invoiced*: Recipient responsible for this data

Number of Jobs*: Recipient responsible for this data

Description of Jobs Created*: Recipient responsible for this data

Quarterly Activities/Project Description*: Recipient responsible for this data

Activity Code (NAICS or NTEE-NPC)*: Recipient responsible for this data

Total Federal Amount of ARRA Expenditure* (Enter the cumulative total amount of Recovery Funds received that were expended to projects or activities. Refer to the Data Model for details on how to calculate this amount.): Recipient responsible for this data

Total Federal ARRA Infrastructure Expenditure Recipient responsible for this data

Infrastructure Contact Name: Recipient responsible for this data

Infrastructure Contact Email: Recipient responsible for this data

Infrastructure Contact Phone: Recipient responsible for this data

Infrastructure Contact Phone Ext: Recipient responsible for this data

Infrastructure Contact Street Address 1: CAMPUS BOX 1034

Infrastructure Contact Street Address 2: Not Available

Infrastructure Contact Street Address 3: Recipient responsible for this data

Infrastructure City: SAINT LOUIS

Infrastructure State: MO

Infrastructure ZIP Code+4: 63112

Infrastructure Purpose and Rationale (If applicable, enter an explanation about how the infrastructure investment will contribute to one or more purposes of the Recovery Act. Refer to the Data Model for details on what to report. 4000 characters or less.): Recipient responsible for this data

Primary Place of Performance

Street Address 1: 660 SOUTH EUCLID AVENUE

Street Address 2: ST. LOUIS

City*: ST. LOUIS

State*: MO

ZIP Code+4*: 63110

Congressional District*: Not Available

Country*: US

Recipient Highly Compensated Officers

Prime Recipient Indication of Reporting Applicability*: Recipient responsible for this data

1. Officer Name and Compensation: Recipient responsible for this data
2. Officer Name and Compensation: Recipient responsible for this data
3. Officer Name and Compensation: Recipient responsible for this data
4. Officer Name and Compensation: Recipient responsible for this data
5. Officer Name and Compensation: Recipient responsible for this data

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