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LOSS OF SIMPL INCREASES TNFα SENSITIVITY DURING HEMATOPOIESIS

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Title: LOSS OF SIMPL INCREASES TNFα SENSITIVITY DURING HEMATOPOIESIS
Author: Benson, Eric Ashley
Advisor: Harrington, Maureen A.
Degree: Ph.D.
Department: Department of Biochemistry & Molecular Biology
Grantor: Indiana University
Permanent Link: http://hdl.handle.net/1805/1851
Abstract: The innate and adaptive immune responses are critical for host survival. The TNFα/NF-κB signaling pathway is a major regulator of the immune response. The TNFα/NF-κB signaling pathway has also been proposed to play a role in the regulation of hematopoiesis. In the TNFα signaling pathway, full induction of NF-κB (specifically the p65 subunit) dependent transcription is regulated by a co-activator SIMPL. The biological significance of SIMPL in TNFα dependent responses is poorly understood. To study SIMPL in vitro and in vivo in mammalian cells, a knockdown system utilizing shRNA (short hairpin RNA) was used. Analysis of hematopoietic progenitor cells infected with a retrovirus encoding the SIMPL shRNA was used to study the role of SIMPL in hematopoiesis. The ability of progenitor cells lacking SIMPL to grow and differentiate was not compromised. In contrast in the progenitors cells lacking SIMPL, TNFα mediated inhibition of colony formation was significantly enhanced. These growth inhibitory effects of SIMPL were not due to an increase in apoptosis. The enhanced inhibitory affects were specific for TNFα and not found in other common hematopoietic inhibitors (TGF-β1 and IFNγ). Results of this work reveal that SIMPL is a component of the hematopoiesis that is required for TNFα dependent effects upon myeloid progenitors.
Keywords: TNFalpha
Hematopoiesis
p65/p50
NF-kappaB
hematopoietic progenitor
CFU-GM
SIMPL
colony assay
hematopoietic stem cell
LC Subject: SIMPL
Hematopoiesis
Date: 2009-03-18
Description: Indiana University-Purdue University Indianapolis (IUPUI)
Appears in Collections: Biochemistry & Molecular Biology Department Theses and Dissertations


 

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