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: 10659020
• 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/10659020
• 关键词: Acceleration; Adopted; Affect; Agonist; American; Anabolism; 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; 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; Postdoctoral Fellow; Production; Property; Proteins; Public Health; Research; Residencies; Resolution; Role; Scientist; Signal Transduction; Strategic Planning; 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; 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; translational potential; 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.

项目总结/文摘