Large Animal Model for Novel Autologous Treatments of Alveolar Clefts

用于新型自体治疗牙槽裂的大型动物模型

• 批准号: 8919541
• 负责人: John Ananda van Aalst
• 金额: $ 12.99万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8919541
• 关键词: 8 year old; Active Learning; Address; Adolescent; Advisory Committees; Algorithms; Alveolar; Animal Model; Animals; Applications Grants; Autologous; Award; Bilateral; Biomechanics; Biomedical Engineering; Bone Marrow; Bone Transplantation; Breathing; Caring; Cell Count; Cell physiology; Cells; Characteristics; Child; Childhood; Cleaved cell; Clinical; Clinical Trials; Clupeidae; Collaborations; Committee Members; Congenital Abnormality; Congenital cerebral hernia; Consultations; Cryopreservation; Data; Defect; Deformity; Dentistry; Dermis; Development; Early treatment; Eating; Effectiveness; Environment; Ethics; Face; Family suidae; Fishes; Foundations; Funding; Future; Generations; Genome; Goals; Grant; Growth; Growth and Development function; Harvest; Healed; Human; Immune; Implant; In Vitro; Individual; Intervention; K-Series Research Career Programs; Knock-out; Knowledge; Lead; Life; Link; Live Birth; Maintenance; Mandible; Marrow; Maxilla; Measures; Mechanics; Mentors; Mesenchymal Stem Cells; Modeling; National Institute of Dental and Craniofacial Research; Natural History; Operative Surgical Procedures; Osteoblasts; Outcome; Pain; Parents; Patients; Physicians; Play; Population; Price; Procedures; Recording of previous events; Recovery; Research; Research Design; Research Personnel; Research Project Grants; Research Training; Resources; Role; School Dentistry; Schools; Scientist; Secondary to; Skeleton; Societies; Solutions; Source; Stem cells; Surface; Surgeon; Techniques; Temporomandibular Joint; Testing; Therapeutic; Thinking; Time; Tissue Engineering; Training; Translating; Translational Research; Translations; Ultrasonography; Umbilical cord structure; United States National Institutes of Health; Unnecessary Surgery; Veterinarians; Veterinary Medicine; Vision; Work; animal model development; base; bone; bone engineering; bone quality; career; career development; cleft lip and palate; clinical practice; college; comparative; craniofacial; craniofacial microsomia; demographics; experience; functional disability; healing; human subject; improved; in vivo; insight; interest; joint function; knowledge translation; medical schools; member; mineralization; next generation; novel; novel therapeutics; osteogenic; prenatal; psychosocial; public health relevance; reconstruction; repaired; rib bone structure; scaffold; skills; stem cell therapy; tool; treatment strategy

DESCRIPTION (provided by applicant): This grant application titled, "Large Animal Model for Novel Autologous Treatments of Alveolar Clefts" is a Mentored Clinical Scientist Research Career Development Award (K08) application under the guidance of Eric Everett (UNC, School of Dentistry) and Jorge Piedrahita (NCSU, College of Veterinary Medicine). The training and research plan represent outgrowths of the candidate's clinical work and emerging translational research; the research project centers on the most pressing current clinical dilemma faced in Pediatric Craniofacial Surgery: absence of bone. These defects result in profound distortions of facial features, major functional debilities, which, when expressed at the extreme, lead to an inability to eat, speak and breathe, creating immense hurdles to productive integration into society. Starting 4 years ago, the candidate's clinical practice began experiencing an increase in parents seen for prenatal consultations secondary to ultrasound diagnoses of craniofacial deformities--primarily clefts of the lip and palate. Because of these changing demographics and the candidate's interest in translational stem cell therapies, the possibility of using umbilical crd (UC) mesenchymal stem cells (MSCs) for novel therapeutics drew increased interest. Historically, much of the initial discussion with parents centered on the inter-disciplinary and long-term surgical care that would be required by their children. Now, the discussion includes the role that mesenchymal stem cells from their children's umbilical cord may play in future surgical care. The long-term goal of this mentored grant is to improve the algorithm of care for craniofacial deformities, through novel therapeutics generated from UC MSCs. The overall goals of this career development grant are to provide the candidate with the necessary didactic and experiential learning to facilitate his transition to an independent investigator and to develop a surgically created juvenile porcine alveolar cleft model to test novel treatments for the alveolar cleft. Aim I develops the model with the use of rib and cancellous bone grafts. After initiating th model, Aim 2 will test autologous porcine UC MSCs within the surgically created cleft; Aim 3 will compare porcine and human UC MSCs for translation of this knowledge to autologous use of cord MSCs in children. To accomplish the goals of this grant, the candidate has access to a unique collaborative environment that includes Craniofacial Geneticists, Veterinarians, Basic Scientists, and Bioengineers that draw from the resources of the UNC Schools of Medicine and Dentistry, and from the NCSU College of Veterinary Medicine. There are programmatic links between these schools and individuals that will allow on-going interactions with a very diverse group of clinicians and researchers who focus on the craniofacial region. The presence of this broad collaboration has challenged and broadened the candidate's thoughts about solutions to the problems faced by these craniofacial patients. The primary mentor, Eric T. Everett has an established record of NIH funding through NIDCR, and of mentoring scientists; the co-mentor, Jorge Piedrahita, similarly has an established record of NIH funding with a history of mentoring junior scientists. The Research Advisory Committee members, Susan Henning, Nancy Allbritton, Elizabeth Loboa, and Richard Fish, each bring distinct strengths to the Committee. Dr. Henning has a long-history of mentoring surgeon scientists. Dr. Allbritton is a physician scientist who provides an example for the candidate's future career growth and development, and has expertise in bioengineered mechanisms to control single cell function. Dr. Loboa has a broad capacity to perform biomechanical testing of engineered bone. Richard Fish has a long-standing history of work with large animal models. A consultant on the mentored grant, Dr. Sue Herring, has significant experience with porcine models to test craniofacial treatment strategies. The members of the Research Advisory Committee are accomplished researchers in their respective fields and will provide insights into the porcine animal model, manipulating mesenchymal stem cells, and measuring mechanical characteristics of tissue engineered bone on both a micro- and macro- level. The goals during this four-year award period are to become a more accomplished scientist, with deeper understanding of research design, the ethical treatment of human subjects and animals, and a broader vision of the role of stem cell therapeutics and nanotechniques for the purposes of translational biomedical tissue engineering. The four-year framework of the grant will provide the tools and skills to become an independent researcher, and also facilitate development as a mentor for the next generation of surgeon scientists. The candidate will use the training and research accomplished in this award to generate preliminary data for a competitive R01 grant application.

描述（由申请人提供）：这项题为“牙槽裂自体新型治疗的大型动物模型”的资助申请是在埃里克·埃弗雷特（北卡罗来纳大学牙科学院）指导下的临床科学家研究职业发展奖（K08）申请和 Jorge Piedrahita（北卡罗来纳州立大学兽医学院）。培训和研究计划代表候选人临床工作和新兴转化研究的成果；该研究项目的重点是当前小儿颅面外科面临的最紧迫的临床困境：骨骼缺失。这些缺陷会导致面部特征的严重扭曲和主要功能障碍，当这些缺陷表现得极端时，会导致无法进食、说话和呼吸，为有效地融入社会造成巨大障碍。从 4 年前开始，候选人的临床实践中，因超声诊断颅面畸形（主要是唇裂和腭裂）而接受产前咨询的父母数量开始增加。由于人口统计数据的变化以及候选人对转化干细胞疗法的兴趣，使用脐带间充质干细胞（MSC）进行新型疗法的可能性引起了越来越多的兴趣。从历史上看，与家长的最初讨论大多集中在孩子需要的跨学科和长期手术护理上。现在，讨论的内容包括来自孩子脐带的间充质干细胞在未来手术护理中可能发挥的作用。这项资助的长期目标是通过 UC MSC 产生的新型疗法来改进颅面畸形的护理算法。这项职业发展补助金的总体目标是为候选人提供必要的教学和体验式学习，以促进他向独立研究者的过渡，并开发通过手术创建的幼年猪牙槽裂模型，以测试牙槽裂的新疗法。 Aim I 使用肋骨和松质骨移植物开发模型。启动模型后，Aim 2 将测试手术创建的裂口内的自体猪 UC MSC；目标 3 将比较猪和人 UC MSC，以将这些知识转化为儿童自体脐带间充质干细胞的使用。为了实现这笔赠款的目标，候选人可以进入一个独特的协作环境，其中包括颅面遗传学家、兽医、基础科学家和生物工程师，这些环境来自北卡罗来纳大学医学院和牙科学院以及北卡罗来纳州立大学兽医学院的资源药品。这些学校和个人之间存在计划联系，这将允许与专注于颅面部区域的非常多样化的临床医生和研究人员群体进行持续互动。这种广泛合作的存在挑战并拓宽了候选人对这些颅面患者所面临问题的解决方案的想法。主要导师埃里克·T·埃弗雷特 (Eric T. Everett) 拥有通过 NIDCR 为 NIH 提供资助以及指导科学家的良好记录。联合导师豪尔赫·皮德拉希塔 (Jorge Piedrahita) 同样拥有 NIH 资助的既定记录，并拥有指导初级科学家的历史。研究咨询委员会成员苏珊·亨宁 (Susan Henning)、南希·奥尔布里顿 (Nancy Allbritton)、伊丽莎白·洛博亚 (Elizabeth Loboa) 和理查德·菲什 (Richard Fish) 各自为委员会带来了独特的优势。亨宁博士拥有指导外科医生科学家的悠久历史。奥尔布里顿博士是一位医学科学家 他为候选人未来的职业成长和发展提供了范例，并拥有控制单细胞功能的生物工程机制方面的专业知识。 Loboa 博士具有对工程骨进行生物力学测试的广泛能力。理查德·菲什 (Richard Fish) 在大型动物模型方面有着悠久的研究历史。 Sue Herring 博士是该资助项目的顾问，在使用猪模型测试颅面治疗策略方面拥有丰富的经验。研究咨询委员会的成员都是各自领域颇有成就的研究人员，他们将提供对猪动物模型、操纵间充质干细胞以及在微观和宏观层面上测量组织工程骨的机械特性的见解。四年奖励期内的目标是成为一名更有成就的科学家，对研究设计、人类受试者和动物的道德治疗有更深入的了解，并对干细胞疗法和纳米技术在以下方面的作用有更广阔的视野。转化生物医学组织工程。该资助的四年框架将为成为一名独立研究人员提供工具和技能，并促进作为下一代外科医生科学家导师的发展。候选人将利用在该奖项中完成的培训和研究来为竞争性 R01 拨款申请生成初步数据。