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导致宿主介导的牙周组织破坏，因为无法解决炎症。专门的促分解脂质介质 (SPM) 包括脂氧素、分解素、保护素、maresins 及其蛋白质缀合物。在实验模型和临床试验中，人类牙周膜干细胞 (PDLSC) 会释放 SPM 来调节免疫调节和促愈合特性，从而发挥多管齐下的作用，改善炎症相关病理结果。然而，MaR1 诱导组织再生（包括骨骼）的机制尚不明确。采用 LM-SPM 代谢脂质组学和 PDLSC RNA 测序的系统生物学方法，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 增强的治疗潜力。 PDLSC 治疗牙周组织再生并转化为人类，提出了三个具体目标：1）建立 PDLSC 中的 MaR1 生物合成途径。 2) 确定 MaR1 控制组织再生的机制 3a) 证明 MaR1 增强猪的 PDLSC 介导的牙周再生 3b) 阐明 MaR1 对猪的 BMP2-PDLSC 联合治疗的影响。研究将实现 NIDCR 的使命：“支持开发与人类疾病和损伤相关的动物模型，用于口腔和口腔组织再生”颅面复合体，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的博士后研究员。该提案包括全面的指导和培训计划，以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。在美国国立卫生研究院 (NIH) 资助的强大科学家团队的指导下，该提案以候选人之前在干细胞领域的研究为基础。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，该阶段是专门为利用申请人的优势而设计的。开发一条新的研究路径，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，完成这一综合培训计划将使候选人获得一套独特的跨学科知识。技能将使她能够过渡到独立，专门从事基于干细胞的牙周组织再生疗法。