Anti-Inflammatory Mesenchymal Stem Cell Therapy for Dental Applications

牙科应用的抗炎间充质干细胞疗法

• 批准号: 9222738
• 负责人: Kyle Holmberg Vining
• 金额: $ 12.67万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9222738
• 关键词: Acute Disease; Address; Adult; Affect; Alginates; Anti-Inflammatory Agents; Anti-inflammatory; Applied Research; Arts; Basic Science; Behavior; Biocompatible Materials; Biophysics; Bone Marrow; Bone necrosis; Cell Therapy; Cell physiology; Cells; Cellular biology; Chronic; Chronic Disease; Clinical; Coculture Techniques; Collagen; Cues; Dental; Dental Pulp; Dentistry; Dentists; Development Plans; Dimensions; Dinoprostone; Disease; Doctor of Philosophy; Educational process of instructing; Encapsulated; Engineering; Epithelial; Faculty; Fibrosis; Gel; Gene Expression; Genetic Transcription; Goals; Growth and Development function; Health; Health Sciences; Histology; Hour; Human; Hydrogels; IL6 gene; Immunity; Immunohistochemistry; Immunology; Immunosuppressive Agents; Immunotherapy; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Injectable; Injection of therapeutic agent; Injury; Interferon Type II; Jaw; Knowledge; Laboratories; Learning; Malignant Neoplasms; Measures; Mechanics; Mediating; Medicine; Mentored Clinical Scientist Award; Mentors; Mesenchymal Stem Cells; Modeling; Normal tissue morphology; Oral; Oral health; Paracrine Communication; Pathogenesis; Periodontitis; Peroxidases; Pharmaceutical Preparations; Phenotype; Plasticizers; Positioning Attribute; Postdoctoral Fellow; Principal Investigator; Property; Pulpitis; Research; Research Personnel; Rodent; Rodent Model; Schools; Science; Scientist; Sjogren' s Syndrome; Stimulus; Students; Surface; TNF gene; Testing; Therapeutic Uses; Training; Translating; Treatment Efficacy; Universities; Work; base; biophysical analysis; biophysical properties; career development; cell behavior; craniofacial; crosslink; experimental study; extracellular; healing; histological stains; immunoregulation; improved; in vivo; macrophage; mechanical properties; meetings; member; novel; oral immunotherapy; oral mucositis; paracrine; prevent; professor; public health relevance; scaffold; skills; stem cell differentiation; student training; symposium; teacher mentor; tenure track; tissue culture

 DESCRIPTION (provided by applicant): Anti-Inflammatory Mesenchymal Stem Cell Therapy for Dental Applications Dr. Vining is a general dentist and Ph.D. student, training with Professor David Mooney at Harvard School of Engineering and Applied Sciences. Dr. Vining's long-term research goal is to address how biophysical parameters of the extracellular microenvironment can be used to develop novel anti-inflammatory therapies in oral and craniofacial health. Specifically, the proposed research will examine whether mechanical stiffness of the microenvironment can be used to control the anti-inflammatory function of MSCs for therapeutic use in oral and craniofacial health. Dr. Vining is committed to become an independent clinician-scientist, so he seeks this mentored clinical scientist award to further his growth and development as a clinician-scientist in oral health sciences and engineering. The proposed research plan will investigate the hypothesis that hydrogel stiffness can be used to control the anti-inflammatory paracrine function of encapsulated bone marrow-derived MSCs in vitro and to enhance their in vivo function in a rodent dental pulp injury model. In Specific Aim 1, Dr. Vining will examine how the level of mechanical stiffness affects the immunomodulatory secretory and transcriptional behavior of adult human bone marrow-derived MSCs in a collagen-alginate interpenetrating network hydrogel. The MSCs' behavior will be characterized in varying matrix stiffness by measuring expression and secretion of pro- and anti-inflammatory factors. Based on the optimal matrix stiffness in bulk hydrogels from Aim 1, in Specific Aim 2 Dr. Vining will investigate the in vitro functional effects of human bone marrow-derived MSCs on human macrophages M1 versus M2 surface markers. In Specific Aim 3, Dr. Vining will investigate the in vivo anti-inflammatory function of MSCs, which are tuned by the stiffness of their microenvironment to increase secretion of anti-inflammatory factors as shown in Aims 1 - 2. He will test the mechanically-tuned human MSCs in vivo by locally injecting MSCs encapsulated in the hydrogel from Aims 1 - 2 into a rodent dental pulp injury model. MSCs' functional effects on the host inflammatory response will be measured by a myeloperoxidase probe, histology and immunohistochemistry, and gene expression. Despite being widely investigated in medicine, MSC immunotherapies have largely been overlooked in dentistry. Dr. Vining proposes to apply these findings to develop a novel MSC-immunotherapy for oral and craniofacial applications. These aims will have an impact on basic science knowledge by exploring how biophysical cues modulate MSCs' immunomodulatory paracrine signaling. As part of Dr. Vining's career development plan, he will take courses in engineering and applied sciences, as well as cell biology and immunology, to help him achieve his research objectives. Dr. Vining will develop his professional skills through participating in research seminars and study groups and presenting at annual major scientific conferences. Dr. Vining will be mentored by his Ph.D. advisor, Professor Mooney, throughout his Ph.D. thesis via formal, bi-weekly individual meetings. Dr. Kai Wucherpfennig will provide co-mentoring for the immunology aspects of the project. A key component of Dr. Vining's training will involve informal training in the lab via interaction with various members of the Mooney laboratory, and collaborating laboratories at Harvard University. Dr. Vining will learn how to be a good teacher and mentor through teaching activities through Harvard Faculty of Arts and Sciences and School of Engineering and Applied Sciences. This plan lays a framework for Dr. Vining's successful progression from mentored Ph.D. student, to independent post- doctoral researcher, and finally independent principal investigator in a tenure-track academic position.

 描述（由应用提供）：牙科应用的抗炎间充质干细胞疗法Vining博士是普通牙医和博士学位。哈佛大学工程和应用科学学院的David Mooney教授的学生，培训。 Vining博士的长期研究目标是解决如何使用细胞外微环境的生物物理参数来开发口腔和颅面健康中新型的抗炎疗法。具体而言，拟议的研究将检查微环境的机械刚度是否可用于控制MSC在口腔和颅面健康中使用治疗的抗炎功能。 Vining博士致力于成为独立的临床科学家，因此他寻求这一心理临床科学家奖，以进一步发展他作为口腔健康科学和工程学临床科学家的成长和发展。拟议的研究计划将调查以下假设：水凝胶刚度可用于控制封装的骨髓衍生的MSC在体外的抗炎旁分泌功能，并在啮齿动物的牙髓牙髓损伤模型中增强其体内功能。在特定的目标1中，Vining博士将研究机械刚度的水平如何影响成年人类骨髓衍生的MSC在胶原蛋白 - 阿基蛋白互层互化网络水凝胶中的免疫调节秘密和转录行为。 MSC的行为将通过测量促和抗炎因子的表达和分泌来表征不同的基质刚度。基于AIM 1的散装水凝胶中最佳基质刚度，在特定的AIM 2中，Vining博士将研究人骨髓衍生的MSC对人类巨噬细胞M1与M2表面标记的体外功能效应。在特定的目标3中，Vining博士将研究MSC的体内抗炎功能，通过其微环境的刚度增加了抗炎因子的分泌，如目标1-2所示。他将通过在AMSS中局部注射MSC的MSC SSC SSC SSC SSC SSC SSC中的机械调整的人类MSC进行了测试。 MSC对宿主炎症反应的功能作用将通过骨髓过氧化物酶探针，组织学和免疫组织化学和基因表达来衡量。尽管在医学领域进行了广泛的研究，但MSC免疫疗法在很大程度上被牙科忽略了。 Vining博士提出的提议将这些发现用于开发一种用于口服和颅面应用的新型MSC免疫疗法。这些目标将通过探索生物物理提示如何调节MSC的免疫调节旁分泌信号传导来影响基础科学知识。作为Vining博士职业发展计划的一部分，他将参加工程和应用科学的课程，以及细胞生物学和免疫学，以帮助他实现自己的研究目标。 Vining博士将在整个参与研究下水道和研究小组中发展他的专业技能，并在年度大型科学会议上展示。 Vining博士将由他的博士学位考虑顾问，穆尼教授，在他的博士学位上通过正式的，每两周举行的个人会议。 Kai Wucherpfennig博士将为该项目的免疫学方面提供联盟。 Vining博士培训的一个关键组成部分将通过与Mooney实验室的各个成员的互动以及哈佛大学的合作实验室进行互动，包括在实验室中进行非正式培训。 Vining博士将通过哈佛艺术和科学学院以及工程与应用科学学院通过教学活动来学习如何成为一名好老师和心态。该计划为Vining博士从Mandended Ph.D.的成功发展提供了一个框架。学生，独立的博士后研究人员，最后是独立的首席研究员，担任终身任职的学术职位。