Cellular interactions and competition in clonal hematopoiesis
Active Project Grant Awarded Last action
- Award ID
- F30HL172468
- Recipient
-
Baylor College Of Medicine UEI FXKMA43NTV21
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $159,473
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date 95% complete
- Place of performance
- Houston, TX 77030, USA
Award details come from USAspending.gov.
Description
- Abstract
- Clonal hematopoiesis (CH) is the expansion of peripheral blood cells derived from a single mutant hematopoietic stem cell (HSC) in the absence of hematological malignancy. CH is associated with increased risk of several age associated diseases however the disease manifestation and prognosis varies based on which gene is mutated, the variant, and the mutational burden. Most individuals over the age of 55 have at least one detectable clone, and of those, 25% have two or more mutant populations present. Despite this vast and variable health burden, little is known about how interactions between mutant clones influences clonal expansion. The top three genes mutated in CH are epigenetic modifiers DNA methyltransferase 3A (DNMT3A), ten- eleven translocation protein 2 (TET2) and additional SEX comb like 1 (ASXL1). Several independent studies of each mutant clone in isolation have identified that these mutations provide hscs with a survival advantage over wild type hscs in the setting of inflammatory stressors, like infections. Additionally, these mutant clones not only respond to inflammatory stimuli, but are also potent produces of pro-inflammatory cytokines that aids in creating an environment that selects for the survival of the mutant clone. Transcriptionally, CH clones have a mutation- specific resistance to extinction by either attenuating the inflammatory stress response or preventing terminal differentiation. Collectively, these studies suggest DNMT3A, ASXL1 and TET2 deficient clones have a mutation- specific resistance to inflammatory pressures, and they perpetuate this selective advantage by inducing pro- inflammatory states. These studies also suggest that mutant clones and their progeny may impact the expansion of neighboring clones, but such clonal interactions and competition has not been studied. Preliminary experiments show TET2 mutant clonal expansion is impaired when in the presence of ASXL1 and DNMT3A-mutant cells. Interestingly, ASXL1 mutant clonal expansion is unaffected by other mutant clones and remains consistent with the presence or absence of other mutant clones. This unexpected finding suggests unexplored interactions between clones having a mutation-specific effect on clonal expansion. Based on published and preliminary data, i hypothesize that mutations influence the inflammatory microenvironment as well as the transcriptional response to stimuli such that clones behave differently in the presence or absence of other clones. In aim 1, i will characterize clonal competition by measuring clonal expansion of DNMT3A, ASXL1 and TET2 deficient clones when in the presence and absence of other mutant clones following inflammatory challenge. In aim 2, i will utilize single cell RNA sequence and EX vivo culturing experiments to identify interactions underlying clonal expansion between DNMT3A, ASXL1 and TET2 deficient hscs and downstream immune cells. With the successful completion of these aims, i will be able to characterize mutation-specific expansion dynamics of each d-a-t clone and their interaction with other clones. I envision using this information to manipulate clonal dynamics as a future therapeutic modality for CH-associated diseases.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $576 | |
| Amendment | $54,538 | |
| Amendment | $54,538 | |
| Original award | $49,821 |
Quick answers
Who received award F30HL172468?
F30HL172468 was awarded to Baylor College Of Medicine by National Heart Lung and Blood Institute (National Institutes of Health) on February 26, 2025.
How much is award F30HL172468 worth?
$159,473 has been obligated on F30HL172468.
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