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Chemical, Structural and Cell-Signaling Interrogation of 15-Prostanglandin Dehydrogenase in Tissue Repair and Regeneration

15-前列腺素脱氢酶在组织修复和再生中的化学、结构和细胞信号传导研究

基本信息

批准号：
10414952
负责人：
ANDREW A PIEPER
金额：
$ 134.53万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10414952
关键词：
Adult Alleles Backcrossings Binding Biochemistry Biological Availability Biotechnology Bleomycin Bone Marrow Bone Marrow Transplantation Brain CXCL12 gene Cell Fraction Cells Chemicals Collection Colon Complex Cryoelectron Microscopy Cytokine Network Pathway Cytokine Signaling Data Data Set Dinoprostone Disease Disease model Drug Targeting Engineering Enzymes Exclusion Foundations Future Growth Hematopoietic Hippocampus (Brain)Individual Inflammation Injury Joints Kidney Diseases Knock-out Knockout Mice Lead Legal patent Liver LoxP-flanked allele Mediating Methods Microglia Modeling Mouse Strains Mus Neurons Neurosciences Oral Organ Oxidoreductase Partial Hepatectomy Pattern Penetration Peripheral Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Prostaglandins Proteins Publications Pulmonary Fibrosis Recovery Reporting Research Resolution Rodent Role Signal Transduction Signaling Molecule Specificity Spleen Structure Techniques Technology Therapeutic Tissue Model Tissues Trauma Traumatic Brain Injury Ulcer Ulcerative Colitis analog base cell type cognitive function conditional knockout cytokine defined contribution design dextran sulfate sodium induced colitis improved in silico in vivo inhibitor knockout gene mRNA Expression macrophage molecular dynamics mouse model predictive test preservation prevent programs protein expression response scaffold single-cell RNA sequencing small molecule small molecule inhibitor structural biology therapeutic target three dimensional structure tissue regeneration tissue repair

项目摘要

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.

摘要。前列腺素E2 （PGE2）调节多种器官的组织生长和修复。一个守恒的