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Principal Investigator: SANFORD D. MARKOWITZ
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $94,538
Funding agency: National Institute of General Medical Sciences
Abstract. Prostaglandin E2 (PGE2) regulates tissue growth and repair in multiple organs. A conserved
mechanism of synthesis and degradation modulates PGE2 levels in response to trauma, inflammation and
disease. In particular, the enzyme 15-prostaglandin dehydrogenase (15-PGDH) is the main PGE2-degrading
enzyme and therefore a key regulator of tissue repair and regeneration. 15-PGDH is an attractive drug target
for diseases characterized by tissue damage. Our team successfully developed the first small molecule
inhibitors of 15-PGDH with in vivo activities. In rodents, our inhibitors 1) accelerate recovery following bone
marrow transplantation, 2) accelerate recovery from, or prevent, ulcerative colitis, 3) accelerate regrowth of
liver tissue following partial hepatectomy, 4) ameliorate pulmonary fibrosis in a bleomycin-induced disease
model, 5) enhance survival of new hippocampal neurons in adult mice, and 6) preserve cognitive function and
minimize neuronal damage in mice following traumatic brain injury. Independent reports have described
beneficial effects of 15-PGDH inhibition in models of renal disease and pulmonary fibrosis.
We now propose a collaborative chemical, structural and cell-signaling interrogation of the role and activity of
15-PGDH. Our expertise includes medicinal chemistry, biochemistry, neuroscience, pharmacology, and
structural biology. In Aim 1, we will define and exploit the structural basis for inhibition of 15-PGDH by small
molecules. This aims builds on the first cryoEM structure (2.3 Å resolution) of 15-PGDH and two unrelated
scaffolds of low-nM inhibitors of 15-PGDH. Proposed research aims to solve the structure of 15-PGDH in
complex with new small molecule inhibitors or substrate. Computational approaches will be employed to
interrogate substrate/inhibitor binding and the enzymatic mechanism. In Aim 2, we will define the cellular,
protein and cytokine signaling networks that are regulated by 15-PGDH and that are engaged by 15-PGDH
inhibitors to potentiate tissue regeneration and repair. The foundation of this aim includes the first
demonstration of 15-PGDH activity in the brain, the identification of macrophages and microglia as major
reservoirs of 15-PGDH expression in peripheral tissues and brain, respectively, and the discovery of cell and
cytokine networks that respond to inhibiting 15-PGDH. We now propose to use single-cell RNA sequencing to
determine the cell types that express 15-PGDH. Similar approaches will identify the cell-signaling network of
induced cytokines and the cell types activated to express them. These studies will be performed in mice
recovering from injury that have been treated with 15-PGDH inhibitors, along with appropriate controls. Finally,
we will engineer macrophage- and microglia-targeted 15-PGDH knockouts to define the role of 15-PGDH
expression in macrophages and microglia in mediating a conserved, cross-tissue response to PGE2 and 15-
PGDH inhibitors. This data set will provide a foundation for future advancement of therapeutics targeting 15-
PGDH and additional drug targets that modulate tissue regeneration.
Terms: <21+ years old><3-D structure><3-dimensional structure><3D structure><Acceleration><Adult><Adult Human><Alleles><Allelomorphs><Ammon Horn><Backcrossings><Binding><Bioavailability><Biochemistry><Biological Availability><Biological Chemistry><Biotech><Biotechnology><Biotinylation><Bleo><Bleomycin><Body Tissues><Bone Marrow><Bone Marrow Grafting><Bone Marrow Reticuloendothelial System><Bone Marrow Transplant><Bone Marrow Transplantation><Brain><Brain Nervous System><Brain Trauma><CXCL12><CXCL12 gene><CXCL12 protein><Cell Body><Cell Communication and Signaling><Cell Fraction><Cell Signaling><Cells><Chemicals><Chemokine (C-X-C Motif) Ligand 12><Collaborations><Collection><Colon><Complex><Cornu Ammonis><Cryo-electron Microscopy><Cryoelectron Microscopy><Cytokine Network><Cytokine Network Pathway><Cytokine Signal Transduction><Cytokine Signaling><DSS colitis><DSS model><DSS mouse model><DSS-induced acute colitis><DSS-induced colitis><Data><Data Set><Dehydrogenases><Dinoprostone><Disease><Disorder><Drug Targeting><Drugs><Electron Cryomicroscopy><Encephalon><Engineering><Enzyme Gene><Enzymes><Exclusion><Foundations><Future><Generalized Growth><Growth><Hematopoietic><Hippocampus><Hortega cell><Individual><Inflammation><Injury><Intracellular Communication and Signaling><Joints><KO mice><Kidney Diseases><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Lead><Legal patent><Liver><LoxP-flanked allele><Lung Tissue Fibrosis><Macrophage><Maps><Marrow Transplantation><Mediating><Medication><Medicinal Chemistry><Methods><Mice><Mice Mammals><Microglia><Modeling><Molecular Dynamics Simulation><Molecular Interaction><Mouse Strains><Murine><Mus><Mφ><Nephropathy><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neurosciences><Null Mouse><Oral><Organ><Oxidoreductase><Oxidoreductase Gene><PBSF><PGE2><PGE2 alpha><PGE2alpha><Partial Hepatectomy><Patents><Pattern><Pb element><Penetration><Peripheral><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pharmaceutical Preparations><Pharmacology><Physiologic Availability><Pre-B Cell Growth Stimulating Factor><Prostaglandin E2><Prostaglandin E2 alpha><Prostaglandin E2alpha><Prostaglandins><Prostanoids><Proteins><Publications><Pulmonary Fibrosis><Recovery><Reductases><Renal Disease><Reporting><Research><Resolution><Rodent><Rodentia><Rodents Mammals><Role><SCYB12><SDF-1><SDF-1A><SDF-1B><SDF-1alpha><SDF1><SDF1A><SDF1B><Scientific Publication><Sdf1 protein><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Specificity><Spleen><Spleen Reticuloendothelial System><Stromal Cell-Derived Factor 1><Structure><TLSF-A><TLSF-B><TPAR1><Techniques><Technology><Testing><Therapeutic><Tissue Growth><Tissue Model><Tissues><Trauma><Traumatic Brain Injury><Ulcer><Ulcerated Colitis><Ulceration><Ulcerative Colitis><Visualization><adulthood><analog><biological signal transduction><cell type><cognitive function><colitis-induced dysbiosis><conditional knock-out><conditional knockout><cryo-EM><cryoEM><cryogenic electron microscopy><cytokine><defined contribution><design><designing><dextran sulfate sodium colitis><dextran sulfate sodium induced colitis><dextran sulfate sodium model><dextran sulfate sodium mouse model><disease model><disorder model><drug/agent><fibrosis in the lung><floxed><floxed allele><gitter cell><hIRH><heavy metal Pb><heavy metal lead><hemopoietic><hepatic body system><hepatic organ system><hippocampal><improved><in silico><in vivo><inhibitor><injuries><kidney disorder><knockout gene><lung fibrosis><mRNA Expression><mesoglia><microglial cell><microgliocyte><molecular dynamics><mouse model><murine model><neuronal><ontogeny><partial excision of liver><perivascular glial cell><preservation><prevent><preventing><programs><protein expression><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><renal disorder><resolutions><response><scRNA-seq><scaffold><scaffolding><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><small molecular inhibitor><small molecule><small molecule inhibitor><social role><stromal cell-derived factor-1alpha><structural biology><subtotal hepatectomy><therapeutic target><three dimensional structure><tissue regeneration><tissue regrowth><tissue renewal><tissue repair><tissue specific regeneration><traumatic brain damage>