Specialized Proresolving Lipid Mediator-Enhanced Stem Cell Therapy and Tissue Regeneration

专门的溶解脂质介质增强干细胞治疗和组织再生

• 批准号: 10429454
• 负责人: Audrey Rakian
• 金额: $ 16.31万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-05 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10429454
• 关键词: Address; Adopted; Affect; Agonist; American; Animal Model; Animals; Anti-Inflammatory Agents; Area; Autologous; BMP2 gene; Bacterial Infections; Binding; Biochemical Process; Bone Marrow; Bone Transplantation; CD59 Antigen; Cells; Chronic; Clinical; Clinical Trials; Comparative Study; Craniofacial Abnormalities; Data; Dental; Dentists; Development; Enzyme Inhibitor Drugs; Etiology; Exhibits; Experimental Models; Family suidae; Funding; GPR6 gene; Goals; Health; Homeostasis; Human; Immunology; Inflammation; Inflammatory; Inflammatory Response; Injury; Investigation; Knowledge; Learning; Leucine-Rich Repeat; Lipoxins; Mediating; Mediator of activation protein; Mentors; Mentorship; Metabolism; Mission; National Institute of Dental and Craniofacial Research; Natural regeneration; Operative Surgical Procedures; Oral; Osteoblasts; Pain; Pathology; Pathway interactions; Periodontal Diseases; Periodontal Ligament; Periodontitis; Periodontium; Phase; Population; Positioning Attribute; Production; Property; Proteins; Public Health; Research; Residencies; Resolution; Role; Scientist; Signal Transduction; System; Systems Biology; Technology; Testing; Texas; Tissues; Tooth Tissue; Training; Translational Research; Translations; Trauma; United States; United States National Institutes of Health; Universities; adult stem cell; alveolar bone; antagonist; base; biological systems; bone; bone healing; chronic inflammatory disease; clinical practice; craniofacial complex; cytokine; design; dysbiosis; gene regulatory network; healing; human disease; human stem cells; immunoregulation; implantation; improved outcome; inflammatory milieu; innovation; lipid mediator; novel; oral microbiome; osteogenic; osteoprogenitor cell; porcine model; preference; receptor; regeneration model; regenerative; regenerative approach; regenerative therapy; regenerative tissue; response; self-renewal; skills; stem cell biomarkers; stem cell therapy; stem cells; success; therapeutic evaluation; tissue regeneration; tissue repair; transcriptome sequencing; translation to humans; wound healing

PROJECT SUMMARY/ABSTRACT Periodontal disease remains a significant public health problem. Chronic unresolved inflammation in response to proinflammatory oral microbiome dysbiosis induces host-mediated destruction of the periodontal tissues. Periodontal regeneration efforts have shown limited success due to the inability to resolve inflammation. Resolution of inflammation is initiated by Specialized Proresolving lipid Mediators (SPMs). SPMs include the lipoxins, resolvins, protectins, maresins, as well as their protein conjugates, which exhibit multipronged actions that improve the outcome of inflammation-related pathologies in experimental models and clinical trials. Human periodontal ligament stem cells human (PDLSC) release SPMs to regulate immunomodulatory and pro-healing properties. Among SPMs, Maresin 1 (MaR1) displays potent actions in regulating inflammation resolution and pain, wound repair and tissue regeneration. However, there is no defined mechanism by which MaR1 induces tissue regeneration, including bone. Our proposed research will address this gap by using a systems biology approach with LM-SPM metabolipidomics, and RNA-sequencing of PDLSC to discover possible pathways modulated by MaR1 in PDLSC tissue regeneration. By utilizing the American Yorkshire Pig as a large animal regeneration model, we will test the therapeutic potential of MaR1-enhanced PDLSC therapy for regeneration of periodontal tissues for translation to humans. Three specific aims are proposed: 1) To establish MaR1 biosynthetic pathway in PDLSC. 2) To define the mechanism by which MaR1 controls tissue regeneration. 3a) To demonstrate MaR1-enhanced PDLSC-mediated periodontal regeneration in the Pig. 3b) To elucidate the impact of MaR1 on combined BMP2-PDLSC treatment in the Pig. Results from these studies will address a mission of NIDCR: ”to support the development of human disease- and injury-relevant animal models for tissue regeneration of the oral and craniofacial complex, with preference given to large animal models.” The candidate is a dentist-scientist and is currently a postdoctoral research fellow at the University of Texas Health San Antonio. This proposal includes a comprehensive mentorship and training plan to advance the candidate’s skills and knowledge in immunology, metabolipidomics, RNA-sequencing and translational science under the guidance of a strong team of NIH-funded scientists; Dr. Kenneth Hargreaves, Dr. Stephen Harris, Dr. Charles Serhan and Dr. George Huang. The proposal builds on the candidate’s previous research in stem cells, BMP2 and periodontium formation by integrating new areas of expertise. The plan includes a mentored phase designed to optimize learning and acquisition of new skills (K99) followed by the R00 phase, which is specifically designed to capitalize on the strengths of the applicant to develop a new path of research that will determine the role of resolution of inflammation and stem cells in BMP2 mediated regeneration. The R00 phase also includes residency training. Completion of this comprehensive training plan will position the candidate with a unique set of cross disciplinary skills that will enable her to transition to independence specializing in stem cell-based periodontal tissue regenerative therapies.

项目概要/摘要 牙周病仍然是一个重要的公共卫生问题。促炎性口腔微生物群失调引起的慢性未解决的炎症会诱导宿主介导的牙周组织破坏。由于无法解决炎症，牙周再生努力的成功有限。炎症的消退是由专门的促消解脂质介质 (SPM) 启动的。 SPM 包括脂氧素、分解素、保护素、maresins 及其蛋白质缀合物，它们表现出多管齐下的作用，可改善实验模型和临床试验中炎症相关病理结果。人牙周膜干细胞 (PDLSC) 释放 SPM 来调节免疫调节和促愈合特性。在 SPM 中，Maresin 1 (MaR1) 在调节炎症消退和疼痛、伤口修复和组织再生方面表现出有效的作用。然而，MaR1 诱导组织再生（包括骨再生）的机制尚无明确。我们提出的研究将通过使用系统生物学方法与 LM-SPM 代谢脂质组学和 PDLSC RNA 测序来解决这一差距，以发现 MaR1 在 PDLSC 组织再生中调节的可能途径。通过利用美国约克夏猪作为大型动物再生模型，我们将测试 MaR1 增强的 PDLSC 疗法在牙周组织再生方面的治疗潜力，并转化为人类。提出了三个具体目标：1）在PDLSC中建立MaR1生物合成途径。 2) 明确MaR1控制组织再生的机制。 3a) 证明 MaR1 增强的 PDLSC 介导的猪牙周再生。 3b) 阐明 MaR1 对猪 BMP2-PDLSC 联合治疗的影响。这些研究的结果将实现 NIDCR 的使命：“支持开发与人类疾病和损伤相关的动物模型，用于口腔和颅面复合体的组织再生，优先考虑大型动物模型。” 该候选人是一名牙医科学家，目前是德克萨斯大学圣安东尼奥分校健康分校的博士后研究员。该提案包括全面的指导和培训计划，以在 NIH 资助的强大科学家团队的指导下提高候选人在免疫学、代谢脂组学、RNA 测序和转化科学方面的技能和知识；肯尼思·哈格里夫斯博士、斯蒂芬·哈里斯博士、查尔斯·瑟汉博士和乔治·黄博士。该提案以候选人之前在干细胞、BMP2 和牙周组织形成方面的研究为基础，整合了新的专业知识领域。该计划包括一个指导阶段，旨在优化新技能的学习和获取（K99），随后是 R00 阶段，该阶段专门设计用于利用申请人的优势开发一条新的研究路径，该路径将确定炎症消退和干细胞在 BMP2 介导的再生中的作用。 R00 阶段还包括住院医师培训。完成这项全面的培训计划将使候选人具备一套独特的跨学科技能，使她能够过渡到独立专业从事基于干细胞的牙周组织再生疗法。