Regulation of emergency hematopoiesis by the ubiquitin-proteasome system

Ended Project Grant Awarded Last action

Award ID
R01HL159175
Recipient
Awarding agency
Obligated
$4,490,052

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date
Funding
  • $3,836,807.00 Federal
  • $653,245.00 Non-federal
Place of performance
Pennsylvania, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
The response to systemic infection and tissue injury requires the rapid adaptation of hematopoietic stem cells (HSCS) in the bone marrow, which proliferate and divert their differentiation towards the myeloid lineage. Significant interest has emerged in understanding the signals that trigger this emergency hematopoietic program. However, the mechanisms that terminate this response of the HSCS and restore tissue homeostasis remain unknown. The clinical success of proteasome inhibitors, bortezomib, and E3 ubiquitin ligase glues for the treatment of hematologic diseases has made the ubiquitin pathway a bona fide target for cancer therapeutics. Thus, defining how novel E3 ligases function in the bone marrow and investigating their specific roles in normal and emergency hematopoiesis can lead to novel therapeutic interventions. We have demonstrated that the E3 ubiquitin ligase spop restrains the inflammatory activation of HSCS. In the absence of spop, systemic inflammation proceeds in an unresolved manner and the sustained response in the HSCS results in a lethal phenotype reminiscent of hyper-inflammatory syndrome. Our proteomic/biochemical studies demonstrated that spop restricts inflammation by targeting the signal transducer MYD88 for proteasome-dependent degradation. MYD88 accumulation in conjunction with an inflammatory stimulus leads to myddosome formation, the hyper-phosphorylation of the IRAK4 kinase and activation of a number of transcription factor pathways (NF-KB, JUN, PU.1, cebpb). This proposal defines: (a) the transcriptional and chromatin landscape changes imposed during initiation and termination of emergency hematopoiesis in the bone marrow HSC and progenitor cells, (B) the role of the myddosome assembly, signaling and termination in emergency hematopoiesis and gene regulation and (C) the structural details of myddosome assembly and termination. The findings of this grant proposal will uncover HSC-intrinsic mechanisms essential for reestablishing homeostasis following emergency hematopoiesis.

Transactions

Action Federal Non-federal Date
Amendment $0 $0
Amendment $615,348 $0
Amendment $627,906 $0
Amendment $633,818 $0
Amendment $653,245 $0
Amendment $653,245 $0
Original award $653,245 $653,245

Subawards

Subrecipient Amount Awarded
University Of Leeds Goals of Agreement The Goals of this proposal are the following: a) defines the Cryo-EM structure of the myddososme with Spop b) defines the Cryo-EM structure… $15,230
New York University Objective 1: Define the SPOP:MYD88 axis in the induction and resolution of inflammation. Description: In this Aim we will study the molecular switch initiated… $307,616
University Of Leeds Goals of Agreement The Goals of this proposal are the following: a) defines the Cryo-EM structure of the myddososme with Spop b) defines the Cryo-EM structure… $15,542

Quick answers

Who received award R01HL159175?

R01HL159175 was awarded to The Trustees Of The University Of Pennsylvania by National Heart Lung and Blood Institute (National Institutes of Health) on September 1, 2021.

How much is award R01HL159175 worth?

$4,490,052 has been obligated on R01HL159175: $3,836,807 in federal funding and $653,245 in non-federal funding.

On GovTribe

See this award's full record

  • Every transaction and subaward
  • The recipient's other awards and teaming partners
  • Similar grant awards
  • Ask GovTribe AI about this award
Try for free Login