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:10627860
- 负责人:
- 金额:$ 135.45万
- 依托单位:
- 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:
- 关键词:AccelerationAdultAllelesBackcrossingsBindingBiochemistryBiological AvailabilityBiotechnologyBiotinylationBleomycinBone MarrowBone Marrow TransplantationBrainCell FractionCellsChemicalsCollaborationsCollectionColonComplexCryoelectron MicroscopyCytokine Network PathwayCytokine SignalingDataData SetDinoprostoneDiseaseDisease modelDrug TargetingEngineeringEnzymesExclusionFoundationsFutureGrowthHematopoieticHippocampusIndividualInflammationInjuryJointsKidney DiseasesKnock-outKnockout MiceLeadLegal patentLiverLoxP-flanked alleleMacrophageMapsMediatingMethodsMicrogliaModelingMouse StrainsMusNeuronsNeurosciencesOralOrganOxidoreductasePartial HepatectomyPatternPenetrationPeripheralPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyProstaglandinsProteinsPublicationsPulmonary FibrosisRecoveryReportingResearchResolutionRodentRoleSignal TransductionSignaling MoleculeSpecificitySpleenStromal Cell-Derived Factor 1StructureTechniquesTechnologyTestingTherapeuticTissue ModelTissuesTraumaTraumatic Brain InjuryUlcerUlcerative ColitisVisualizationanalogcell typecognitive functionconditional knockoutcytokinedefined contributiondesigndextran sulfate sodium induced colitisimprovedin silicoin vivoinhibitorknockout genemRNA Expressionmolecular dynamicsmouse modelpreservationpreventprogramsprotein expressionresponsescaffoldsingle-cell RNA sequencingsmall moleculesmall molecule inhibitorstructural biologytherapeutic targetthree dimensional structuretissue regenerationtissue 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) 调节多个保守器官的组织生长和修复。
合成和降解机制调节 PGE2 水平以应对创伤、炎症和炎症
特别是,15-前列腺素脱氢酶(15-PGDH)是主要的 PGE2 降解酶。
因此,15-PGDH 是组织修复和再生的关键调节剂,是一个有吸引力的药物靶标。
针对以组织损伤为特征的疾病,我们的团队成功开发了第一个小分子。
具有体内活性的 15-PGDH 抑制剂,在啮齿动物中,我们的抑制剂 1) 加速骨后恢复。
骨髓移植,2) 加速溃疡性结肠炎的恢复或预防,3) 加速骨髓的再生
部分肝切除术后的肝组织,4) 改善博莱霉素诱发疾病的肺纤维化
模型,5)增强成年小鼠新海马神经元的存活率,6)保留认知功能和
独立报告描述了减少小鼠脑外伤后的神经损伤。
15-PGDH 抑制对肾病和肺纤维化模型的有益作用。
我们现在提出对以下物质的作用和活性进行协作化学、结构和细胞信号转导询问:
我们的专业知识包括药物化学、生物化学、神经科学、药理学和 15-PGDH。
在目标 1 中,我们将定义并开发小分子抑制 15-PGDH 的结构基础。
该目标建立在 15-PGDH 的第一个冷冻电镜结构(2.3 Å 分辨率)和两个不相关的分子的基础上。
15-PGDH 低 nM 抑制剂的支架 拟议的研究旨在解决 15-PGDH 的结构。
与新的小分子抑制剂或底物的复合物将被采用计算方法。
探究底物/抑制剂结合和酶促机制 在目标 2 中,我们将定义细胞、
受 15-PGDH 调节并受 15-PGDH 参与的蛋白质和细胞因子信号传导网络
该目标的基础包括第一个目标。
证明大脑中 15-PGDH 活性,确定巨噬细胞和小胶质细胞是主要的
15-PGDH 分别在外周组织和脑中表达的储存库,以及细胞和
我们现在建议使用单细胞 RNA 测序来对抑制 15-PGDH 做出反应。
确定表达 15-PGDH 的细胞类型将识别 15-PGDH 的细胞信号网络。
诱导的细胞因子和激活表达它们的细胞类型这些研究将在小鼠中进行。
使用 15-PGDH 抑制剂治疗的损伤正在恢复,并进行适当的对照。
我们将设计针对巨噬细胞和小胶质细胞的 15-PGDH 敲除,以定义 15-PGDH 的作用
巨噬细胞和小胶质细胞中的表达介导对 PGE2 和 15- 的保守跨组织反应
该数据集将为 15- 靶向治疗的未来发展奠定基础。
PGDH 和调节组织再生的其他药物靶点。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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SANFORD D. MARKOWITZ其他文献
SANFORD D. MARKOWITZ的其他文献
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{{ truncateString('SANFORD D. MARKOWITZ', 18)}}的其他基金
Targeting 15-Prostaglandin Dehydrogenase (15-PGDH) in Cancer Risk, Prevention, and Treatment
针对癌症风险、预防和治疗中的 15-前列腺素脱氢酶 (15-PGDH)
- 批准号:
9406781 - 财政年份:2016
- 资助金额:
$ 135.45万 - 项目类别:
Targeting 15-Prostaglandin Dehydrogenase (15-PGDH) in Cancer Risk, Prevention, and Treatment
针对癌症风险、预防和治疗中的 15-前列腺素脱氢酶 (15-PGDH)
- 批准号:
10524057 - 财政年份:2016
- 资助金额:
$ 135.45万 - 项目类别:
Targeting 15-Prostaglandin Dehydrogenase (15-PGDH) in Cancer Risk, Prevention, and Treatment
针对癌症风险、预防和治疗中的 15-前列腺素脱氢酶 (15-PGDH)
- 批准号:
10305660 - 财政年份:2016
- 资助金额:
$ 135.45万 - 项目类别:
Targeting 15-Prostaglandin Dehydrogenase (15-PGDH) in Cancer Risk, Prevention, and Treatment
针对癌症风险、预防和治疗中的 15-前列腺素脱氢酶 (15-PGDH)
- 批准号:
10058813 - 财政年份:2016
- 资助金额:
$ 135.45万 - 项目类别:
Targeting 15-Prostaglandin Dehydrogenase (15-PGDH) in Cancer Risk, Prevention, and Treatment
针对癌症风险、预防和治疗中的 15-前列腺素脱氢酶 (15-PGDH)
- 批准号:
9183207 - 财政年份:2016
- 资助金额:
$ 135.45万 - 项目类别:
Role of gene enhancer elements in colon cancer
基因增强子元件在结肠癌中的作用
- 批准号:
8449075 - 财政年份:2012
- 资助金额:
$ 135.45万 - 项目类别:
Role of gene enhancer elements in colon cancer
基因增强子元件在结肠癌中的作用
- 批准号:
8289140 - 财政年份:2012
- 资助金额:
$ 135.45万 - 项目类别:
Role of gene enhancer elements in colon cancer
基因增强子元件在结肠癌中的作用
- 批准号:
8633432 - 财政年份:2012
- 资助金额:
$ 135.45万 - 项目类别:
Targeting 15-PGDH in Colon Cancer Prognosis, Prediction, Treatment and Prevention
以 15-PGDH 为靶点进行结肠癌的预后、预测、治疗和预防
- 批准号:
8555227 - 财政年份:2011
- 资助金额:
$ 135.45万 - 项目类别:
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