Resolution Mechanisms in Acute Inflammation: Resolution Pharmacology

急性炎症的消退机制：消退药理学

• 批准号: 9906229
• 负责人: Charles Nicholas Serhan
• 金额: $ 160.64万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906229
• 关键词: Acute; Address; Anabolism; Animal Disease Models; Anti-Inflammatory Agents; Back; Biological Models; CD59 Antigen; Cell Communication; Chemicals; Chemotactic Factors; Clinic; Coupled; Critical Pathways; Epithelial Cells; Exudate; Family; Goals; Healthcare; Histology; Homeostasis; Host Defense; Human; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Invaded; Knowledge; Leukocytes; Leukotrienes; Lipoxins; Mediator of activation protein; Mission; Molecular; Natural regeneration; Nosocomial Infections; Operative Surgical Procedures; Organ; Organic Synthesis; Organism; Outcome; Pathway interactions; Patient Care; Peptides; Phagocytes; Pharmacology; Phase; Process; Prostaglandins; Public Health; Recovery; Resolution; Role; Severities; Signal Transduction; Strategic Planning; Structure; Surgical Injuries; Testing; Time; Tissues; Trauma; clinical practice; counterregulation; human disease; human tissue; improved; indexing; instrument; interdisciplinary approach; lipid mediator; metabolome; microbial; multidisciplinary; novel; novel therapeutic intervention; programs; public health relevance; tissue injury; tissue regeneration; tool

 DESCRIPTION (provided by applicant): When uncontrolled, infectious inflammation compromises organ function and is associated with many widely occurring human diseases of major public health concern. Surgery, trauma, and tissue injury can enable invading organisms to cause infections and inflammation that, if unresolved, can be fatal. These barrier breaks and microbial invasion evoke acute inflammation that is ideally protective and self-resolving. Resolution of inflammation was believed to occur via passive dilution of chemical mediators and pro-inflammatory molecules. From this Program Project, evidence emerged indicating resolution is an active molecular process orchestrated by new families of specialized pro-resolving mediators (SPM). These structurally distinct families include resolvins (Rv), protectins (PD), maresins (MaR) and their newly discovered potent SPM-sulfido-conjugates (SC) that resolve inflammation and stimulate tissue regeneration (Conjugates in Tissue Regeneration; CTR). Our overall mission in this renewal is to systematically elucidate the structures and functions of nove mediators in resolution and tissue regeneration. Our strategic plan includes lipid mediator (LM)-SPM-metabolipidomics with resolution and regeneration indices to interrogate inflammatory exudates and tissues coupled with total organic synthesis of SPM and SPM-SC standards to validate structure-function. The overarching novel hypothesis to be addressed by each project of this renewal requires a highly multi-disciplinary team and approach. Together, we shall test the following: Infectious inflammatory exudates evoked by tissue injury, surgical trauma and infection emit potent soluble chemical mediators locally such as SPM and their newly identified sulfido- conjugates that actively orchestrate resolution of inflammation, enhance microbial killing and clearance, as well as tissue regeneration. These new molecular resolution programs are essential for host defense and dictate severity and recovery intervals. This program project team is configured to address these unmet challenges and consists of 3 highly interactive projects, 2 scientific cores and an administrative core with expert advisory panels focused on establishing lipid mediator-resolution functional metabolome, stereo-controlled synthesis of SPM, SPM-SC and their specific mechanisms in resolution of infectious inflammation and clearance pathways. Our broad goal is to harness these molecules and pathways to bring forth resolution pharmacology for new treatments to control infectious inflammation and related tissue damage.

 描述（由适用提供）：当不受控制的感染感染损害器官功能时，并且与许多广泛发生的主要公共卫生关注的人类疾病有关。手术，创伤和组织损伤可以使入侵的生物能够引起感染和炎症，如果未解决，可能是致命的。这些障碍断裂和微生物侵袭引起了理想保护和自我解决的急性炎症。据信炎症的分辨率是通过被动稀释化学介质和促炎性分子而发生的。从这个计划项目中，出现了表明分辨率的证据是由专业支持的介体（SPM）的新家族策划的一个主动分子过程。这些在结构上不同的家族包括分辨（RV），保护素（PD），Maresins（Mar）及其新发现的潜在的SPM-硫磺偶联物（SC），这些SCLFIDO-CONJUGATES（SC）可以解决炎症并刺激组织再生（组织再生中的结合物； CTR）。我们在这种更新中的总体任务是系统地阐明新型介体在分辨率和组织再生中的结构和功能。我们的战略计划包括具有分辨率和再生指数的脂质介体（LM）-SPM-SPM量代谢，以询问炎症性渗出液和组织以及SPM和SPM-SC标准标准的总有机合成以验证结构功能。该续签的每个项目要解决的总体小说假设需要一个高度多学科的团队和方法。我们将共同测试以下内容：感染性炎症性散发出因组织损伤，手术创伤和感染引起的诱发的散发器，散发出当地的潜在固体化学介质，例如SPM及其新鉴定的硫化偶联物，这些硫化物偶联会积极控制感染的分辨率，增强微生物杀死的抑制作用 和清除以及组织修订。这些新的分子分辨率计划对于宿主防御至关重要，决定了严重性和恢复间隔。该计划项目团队的配置为解决这些未满足的挑战，并由3个高度互动的项目，2个科学核心和一个管理核心组成，其专家咨询面板旨在建立脂质介体分辨率的功能代谢，立体控制，SPM SPM，SPM-SC，SPM-SC，SPM-SC及其特定机制及其在感染性感染patectionallance Patection和Cleartection Patection patectionally中的特定机制。我们的广泛目标是利用这些分子和途径，为新疗法提供分辨率，以控制感染感染和相关的组织损伤。

项目成果

Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rabbit vein graft model.

• DOI: 10.1016/j.jvs.2018.05.206
• 发表时间: 2018-12
• 期刊: Journal of vascular surgery
• 影响因子: 4.3
• 作者: Wu B;Werlin EC;Chen M;Mottola G;Chatterjee A;Lance KD;Bernards DA;Sansbury BE;Spite M;Desai TA;Conte MS
• 通讯作者: Conte MS

Proresolving receptor tames inflammation in atherosclerosis.

促解受体可抑制动脉粥样硬化中的炎症。

• DOI: 10.1172/jci155240
• 发表时间: 2021
• 期刊: The Journal of clinical investigation
• 作者: Mena,HebeAgustina;Spite,Matthew
• 通讯作者: Spite,Matthew

Synthesis of protectin D1 analogs: novel pro-resolution and radiotracer agents.

保护素 D1 类似物的合成：新型促解析剂和放射性示踪剂。

• DOI: 10.1039/c8ob01232f
• 发表时间: 2018
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2
• 作者: Tungen,JE;Aursnes,M;Ramon,S;Colas,RA;Serhan,CN;Olberg,DE;Nuruddin,S;Willoch,F;Hansen,TV
• 通讯作者: Hansen,TV

Resolving Inflammation: Synthesis, Configurational Assignment, and Biological Evaluations of RvD1n-3 DPA.

解决炎症：RvD1n-3→DPA 的合成、构型分配和生物学评估。

• DOI: 10.1002/chem.201806029
• 发表时间: 2019
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Tungen,JørnEivind;Gerstmann,Lisa;Vik,Anders;DeMatteis,Roberta;Colas,RomainAlexandre;Dalli,Jesmond;Chiang,Nan;Serhan,CharlesNicholas;Kalesse,Markus;Hansen,TrondVidar
• 通讯作者: Hansen,TrondVidar

Total synthesis of the lipid mediator PD1n-3 DPA: configurational assignments and anti-inflammatory and pro-resolving actions.

• DOI: 10.1021/np4009865
• 发表时间: 2014-04-25
• 期刊: Journal of natural products
• 影响因子: 5.1
• 作者: Aursnes M;Tungen JE;Vik A;Colas R;Cheng CY;Dalli J;Serhan CN;Hansen TV
• 通讯作者: Hansen TV