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Inflammation-Induced HSPC Dysfunction: Towards a Better Understanding of the Role of MAVS, ASC, and Caspase-1 in HSPC Dysfunction and Bone Marrow Failure

David, Dylan Naitraj
http://orcid.org/0000-0002-6821-9071
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1626356668978688

Abstract Details

2021, MS, University of Cincinnati, Medicine: Immunology.
Bone marrow failure (BMF) syndromes, such as myeloid dysplastic syndrome (MDS), can arise from acute or chronic inflammatory events that cause ineffective hematopoiesis, driving cytopenia in different blood cell lineages. One central question in the field is to understand the causal contribution of inflammation to the development of BMF. Our lab and others have shown that increased TGFß1 signaling causes ineffective hematopoiesis. TGFß1 is known to be elevated in patients with MDS. Further understanding of these mechanisms using a conditional aTGFß1-overexpressing transgenic mouse model (Tg-Cre+) demonstrated that elevated TGFß1 signaling cooperates with activation of innate immune signaling, triggered by acute polyinosinic:polycytidylic acid (pIC) challenge, and causes MDS-like phenotype within 3 months of pIC exposure that worsens over one year. Analysis of Tg-Cre+ HSPCs 3 months after pIC stress suggests that a MAVS-NLRP3 inflammasome signaling axis downstream of aTGFß1-overexpression may drive the BMF phenotypes in the mouse model, indicated by increased MAVS and ASC activation, as ASC is an essential subunit of the NLRP3 inflammasome. We therefore hypothesized that in response to acute inflammatory stress, HSPCs activate a non-canonical MAVS-ASC-NLRP3 signaling axis that drives ineffective hematopoiesis. To this end, this study focuses on the correlation between HSPC dysfunction and the role of downstream effectors, such as MAVS, ASC, and caspase-1. In this study, we utilized flow cytometry and immunofluorescence assays to analyze the HSPC pool, ASC speckling and activation, and caspase-1 activation in response to different doses of pro-inflammatory agents in genetically varied mouse models. Our data shows that inflammation-induced HSPC expansion is, at least in part, MAVS-dependent and ASC-dependent, underscoring a novel potential mechanism of inflammation-driven BMF/MDS-like diseases.
Marie-Dominique Filippi, Ph.D. (Committee Chair)
Jonathan Katz, Ph.D. (Committee Member)
Chandrashekhar Pasare, DVM PhD (Committee Member)
54 p.
Immunology
Immunology; HSPC; HSPC; Inflammasome; ASC; MAVS

Recommended Citations

Citations

  • David, D. N. (2021). Inflammation-Induced HSPC Dysfunction: Towards a Better Understanding of the Role of MAVS, ASC, and Caspase-1 in HSPC Dysfunction and Bone Marrow Failure [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1626356668978688

    APA Style (7th edition)

  • David, Dylan. Inflammation-Induced HSPC Dysfunction: Towards a Better Understanding of the Role of MAVS, ASC, and Caspase-1 in HSPC Dysfunction and Bone Marrow Failure. 2021. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1626356668978688.

    MLA Style (8th edition)

  • David, Dylan. "Inflammation-Induced HSPC Dysfunction: Towards a Better Understanding of the Role of MAVS, ASC, and Caspase-1 in HSPC Dysfunction and Bone Marrow Failure." Master's thesis, University of Cincinnati, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1626356668978688

    Chicago Manual of Style (17th edition)

ucin1626356668978688
69
© 2021, some rights reserved.Creative Commons License Inflammation-Induced HSPC Dysfunction: Towards a Better Understanding of the Role of MAVS, ASC, and Caspase-1 in HSPC Dysfunction and Bone Marrow Failure by Dylan Naitraj David is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.