Determining how inflammation is regulated in RUNX1-familial platelet disorder with associated myeloid malignancies
Active Project Grant Awarded Last action
- Award ID
- F30HL178182
- Recipient
-
The Trustees Of The University Of Pennsylvania UEI GM1XX56LEP58
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $163,626
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date 42% complete
- Place of performance
- Philadelphia, PA 19104, USA
Award details come from USAspending.gov.
Description
- Abstract
- RUNX1 familial platelet disorder with associated myeloid malignancies (RUNX1-FPD) is caused by inherited monoallelic mutations in the RUNX1 transcription factor. RUNX1-FPD patients have a high risk of developing hematologic malignancies. Chronic inflammation is thought to play a central role in driving the risk for cancer in RUNX1-FPD. As such, controlling inflammation may be an effective therapeutic strategy for preventing cancer. However, the mechanisms by which mutations in RUNX1 promote an inflammatory state are incompletely understood. We previously showed using genetic mouse models that loss of RUNX1 epigenetically derepresses inflammatory signaling pathways in granulocyte-monocyte progenitors (gmps). These epigenetic alterations are inherited by neutrophils, which become primed to oversecrete cytokines. The epigenetic state induced by loss of RUNX1 in gmps strikingly resembles the proinflammatory epigenetic state of hematopoietic stem and progenitor cells (hspcs) in trained innate immunity (TII). In TII, exposure to pathogen or damage associated molecular patterns induces hspcs to undergo epigenetic remodeling that enables the innate immune system to respond to these stimuli more robustly in the future. In contrast to the adaptive nature of TII, complete loss of RUNX1 appears to induce a fixed and maladaptive proinflammatory state. The first goal of this proposal is to establish whether RUNX1-FPD patients exhibit a state of fixed maladaptive innate immunity. The second goal of this proposal is to determine whether and how the adaptive process of TII is altered in RUNX1-FPD. I hypothesize that fixed maladaptive innate immunity caused by decreased RUNX1 levels in hematopoietic progenitors will augment TII. I will test my hypothesis in a mouse model that faithfully recapitulates RUNX1-FPD using a high FAT diet model to induce TII. These studies will provide mechanistic insight into the dynamic role that RUNX1 plays in regulating the inflammatory potential of the innate immune system and may identify opportunities to therapeutically control inflammation.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $55,114 | |
| Amendment | $564 | |
| Amendment | $53,974 | |
| Original award | $53,974 |
Quick answers
Who received award F30HL178182?
F30HL178182 was awarded to The Trustees Of The University Of Pennsylvania by National Heart Lung and Blood Institute (National Institutes of Health) on August 22, 2025.
How much is award F30HL178182 worth?
$163,626 has been obligated on F30HL178182.
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