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.

项目摘要/摘要 牙周病仍然是一个重大的公共卫生问题。慢性未分辨感染响应促炎口腔微生物组营养不良会导致宿主介导的牙周组织的破坏。由于无法解决注射，牙周再生工作已显示出有限的成功。感染的分辨率是由专门的脂质介质（SPM）启动的。 SPM包括脂毒素，溶酶蛋白，保护素，母体及其蛋白结合物，在实验模型和临床试验中，揭示了可改善与感染相关病理学结果的多重作用。人牙周韧带干细胞人类（PDLSC）释放SPM，以调节免疫调节和促愈合特性。在SPMS中，Maresin 1（MAR1）在确定炎症解决和疼痛，伤口修复和组织再生方面显示了潜在的动作。然而，没有确定的机制MAR1诱导组织再生，包括骨骼。我们提出的研究将通过使用LM-SPM代谢型组学的系统生物学方法以及对PDLSC的RNA序列来解决这一差距，以发现MAR1在PDLSC组织再生中调节的可能途径。通过使用美国约克郡猪作为大型动物再生模型，我们将测试MAR1增强PDLSC治疗的治疗潜力，用于牙周组织再生以转化为人类。提出了三个具体目标：1）在PDLSC中建立MAR1生物合成途径。 2）定义MAR1控制组织再生的机制。 3A）证明了猪中MAR1增强的PDLSC介导的牙周再生。 3B）阐明了MAR1对猪中BMP2-PDLSC联合处理的影响。这些研究的结果将涉及NIDCR的任务：“支持人类疾病和损伤的动物模型的发展，用于口腔和颅面复合物的组织再生，偏爱大型动物模型。” 候选人是牙医科学家，目前是德克萨斯大学健康圣安东尼奥分校的博士后研究员。该提案包括一项全面的心态和培训计划，以提高候选人在免疫学，代谢型组学，RNA测序和转化科学方面的技能和知识，并在坚强的NIH资助科学家团队的指导下进行。肯尼斯·哈格里夫斯（Kenneth Hargreaves）博士，斯蒂芬·哈里斯（Stephen Harris）博士，查尔斯·塞尔（Charles Serhan）博士和乔治·黄（George Huang）博士。该提案建立在候选人先前在干细胞，BMP2和牙周形成方面的研究，通过整合新的专业领域。该计划包括一个旨在优化新技能学习和获取的阶段（K99），然后是R00阶段，该阶段专门设计用于利用应用程序的优势，以开发新的研究途径，以确定BMP2介导的再生中炎症和干细胞的分辨率的作用。 R00阶段还包括居住培训。这项全面的培训计划的完成将使候选人拥有一套独特的跨学科技能，这将使她能够过渡到专门研究基于干细胞的牙周组织再生疗法的独立性。