Novel systemic PEGylated NELL-1 therapy for craniofacial osteoporosis

新型系统性聚乙二醇化 NELL-1 疗法治疗颅面骨质疏松症

• 批准号: 9294346
• 负责人: Jin Hee Kwak
• 金额: $ 15.82万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294346
• 关键词: Achievement; Address; Advisory Committees; Affect; Affinity; Alveolar; Alveolar Bone Loss; Animals; Award; Back; Biomedical Engineering; Biomedical Research; Bone Density; Bone Resorption; Bone Tissue; Cephalic; Characteristics; Clinical; Clinical Research; Collaborations; Communities; Data; Dental; Dental Research; Dentures; Development; Dose; Drug Kinetics; Economic Burden; Environment; Event; Faculty; Failure; Formulation; Fostering; Frequencies; Goals; Growth; Half-Life; Hormones; Human Resources; Implant; In Vitro; Injectable; Injection of therapeutic agent; Innovative Therapy; Institution; Interdisciplinary Study; Jaw; Knockout Mice; Link; Maintenance; Mandible; Maxilla; Mentors; Mentorship; Mesoderm; Metabolic Bone Diseases; Molecular; Morbidity - disease rate; Mus; Natural regeneration; Neural Crest; Neural Crest Cell; New Agents; Osteoblasts; Osteoclasts; Osteogenesis; Osteopenia; Osteoporosis; Osteoporotic; Ovariectomy; Paget' s Disease; Patients; Persons; Physiologic Ossification; Plasma; Positioning Attribute; Postmenopause; Proteins; Publications; Research; Research Personnel; Resources; School Dentistry; Scientist; Secure; Signal Transduction; Skeletal Development; Skeleton; Space Flight; Stem cells; Structure; Systemic Therapy; Systemic disease; Testing; Therapeutic; Time; Tissue Engineering; Tooth Loss; Training; Transgenic Organisms; Treatment Efficacy; United States National Aeronautics and Space Administration; Wages; Work; alveolar bone; base; beta catenin; bisphosphonate; bone; bone loss; career; career development; cost; craniofacial; cranium; experience; improved; in vivo; innovation; intramembranous bone formation; long bone; member; multidisciplinary; novel; osteogenic; osteogenic protein; osteoporotic bone; prevent; progenitor; programs; public health relevance; research facility; skills; spine bone structure; standard of care; targeted agent; uptake

PROJECT SUMMARY / ABSTRACT I. Candidate I am a board-certified orthodontist and a research-track faculty at the UCLA School of Dentistry. I am a dual- trained clinician scientist, with significant background in bone tissue engineering with 16 publications, 24 podium abstract presentations, and 6 national-level excellence-in-research awards to date. For the past 7 years I have worked extensively with various transdisciplinary research teams at UCLA, based on which I have sought primary mentorship from Dr. Chia Soo and formed the five-person advisory committee of the current proposal. Under Dr. Soo's new mentorship, I am in the path of establishing a clear independence from my previous and current mentors' work, evidenced by my recent achievements delineated in the current proposal. My immediate career goals are to secure time and effort for research career development by means of a K08 award, continue devising innovations relevant to the Nation's research needs, and build upon my prolific publication record. My end goal is for scientific independence in a tenure faculty position, and to continue addressing the Nation's biomedical and clinical research needs by transdisciplinary efforts. A K08 award will tremendously benefit my career development by providing (i) a structured program to cultivate multidisciplinary research skills, (ii) salary support to maintain commitment to research-track, and (iii) protected research time. The astonishing five-member advisory committee assembled for this proposal consists of developmental and molecular biologists, clinician scientists with FDA experience, and bioengineer to provide mentorship in this highly translational and multidisciplinary project. The distinguished and experienced mentors are composed of leading members of the UCLA research community, and will provide both research and administrative support. In addition to receiving unanimous institutional backing from the School of Dentistry, I will benefit from and strengthen the robust collaboration that exists between my mentors and their research collaborators. II. Environment UCLA is one of the leading public research institutions in the world and provides an excellent academic environment with rich intellectual resources, abundant research facilities, and robust institutional support. The institutional environment at UCLA offers a great wealth of closely integrated and shared physical and human resources that can foster the growth and intellectual development of a young scientific investigator. III. Research Dental osteopenia and its associated morbidities such as tooth loss, periodontal implant failures, and malfitting dentures are projected to cost over $240 billion worldwide by 2040. Therapeutic approaches to osteoporotic bone loss have focused on either anabolic or antiresorptive agents. However, there is a pressing need to develop new agents that target both bone formation and resorption. Importantly, there is no concrete evidence that supports whether an osteoporosis therapy can also prevent the dentoalveolar osteopenia frequently seen in post-menopausal osteoporotic patients. NELL-1 is a potent pro-osteogenic and anti-resorptive protein that was recently found to exert a systemic, protective function against osteoporotic bone loss. PEGylation of NELL-1 (NELL-PEG) has enhanced NELL-1's pharmacokinetics as a systemic therapy. As a result, preliminary studies demonstrate that systemic NELL-PEG regenerates ovariectomy-induced bone loss not only in long bones, but also in maxillary alveolar bone in mice. This has led to our central hypothesis that systemic NELL-PEG therapy can reverse osteoporotic bone loss in both postcranial (appendicular and axial) and craniofacial (cranium, maxilla, and mandible) skeleton. We will test this hypothesis in three specific aims: AIM 1. Determine the pharmacokinetics and the targeting efficiency of NELL-1 and PEGylated NELL-1. In this aim, we will determine the pharmacokinetic profile of systemic NELL-PEG in bone and plasma over an 8-week period. Both postcranial and craniofacial bones will be analyzed. AIM 2. Determine the therapeutic efficacy of PEGylated NELL-1 in regenerating jaw bones alongside postcranial bones in osteoporotic mice. AIM 2A will evaluate the effect of systemic NELL-PEG on craniofacial versus postcranial bones in OVX-induced osteoporotic mice. Previously determined formulations of systemic NELL-PEG will be tested, and bone density, formation, and turnover will be assessed. Concurrently, AIM 2B will evaluate systemic NELL-PEG effects on the number and activity of stem cells, osteoblasts (OB), and osteoclasts (OC) in the mandible, long bone and vertebra. AIM 3. Examine the effects of Nell-1 on craniofacial versus postcranial skeletal development and maintenance in osteoblast-specific transgenic knockout mice. In this aim, we will cross our recently generated Nell-1flox/flox mice with 2.3kb Col1-Cre and Wnt1-Cre to examine osteoblast and neural crest specific effects, respectively. Novel rNELL-1 based therapies can vastly improve the standard of care for the treatment of osteoporosis, dental osteopenia and its morbidities. Development of a systemic therapy that can promote dual anabolic and anti-osteoclastic effects in craniofacial and postcranial bones alike would provide a groundbreaking therapy.

项目总结/摘要 I.候选 我是加州大学洛杉矶分校牙科学院的一名董事会认证的牙医和研究跟踪教师。我是个双重- 训练有素的临床科学家，具有骨组织工程的重要背景，发表过16篇论文，24篇 迄今为止，已获得6项国家级优秀研究奖。过去7 多年来，我与加州大学洛杉矶分校的各种跨学科研究团队进行了广泛的合作，在此基础上， 寻求Chia Soo博士的主要指导，并组建了目前的五人咨询委员会 提议在苏博士的新指导下，我正在建立一个明确的独立性， 以前和现在的导师的工作，证明了我最近的成就，在目前的建议。 我的近期职业目标是通过K 08为研究职业发展争取时间和精力 继续设计与国家研究需求相关的创新，并建立在我多产的基础上。 出版记录。我的最终目标是在一个终身教职的位置上实现科学的独立性，并继续 通过跨学科的努力解决国家的生物医学和临床研究需求。K 08奖项将 通过提供（i）一个结构化的计划，培养多学科的， 研究技能，（二）工资支持，以保持对研究轨道的承诺，和（三）保护研究时间。 令人惊讶的五人咨询委员会为这一建议而聚集， 分子生物学家、具有FDA经验的临床科学家和生物工程师， 高度转化和多学科项目。杰出而经验丰富的导师由 加州大学洛杉矶分校研究界的主要成员，并将提供研究和行政支持。 除了获得牙科学院的一致机构支持外，我还将受益于和 加强我的导师和他们的研究合作者之间的强大合作。 二.环境 加州大学洛杉矶分校是世界领先的公共研究机构之一，并提供了一个优秀的学术 我们拥有丰富的智力资源，丰富的研究设施和强大的机构支持。的 加州大学洛杉矶分校的机构环境提供了大量的紧密结合和共享的物理和人类 这些资源可以促进年轻科学研究人员的成长和智力发展。 三.研究 牙齿骨质减少及其相关疾病，如牙齿脱落、牙周植入失败和不合适 预计到2040年，全世界假牙的成本将超过2400亿美元。骨质疏松症的治疗方法 骨丢失集中在合成代谢或抗吸收剂上。然而，迫切需要 开发针对骨形成和骨吸收的新药物。重要的是，没有具体的证据 支持骨质疏松症治疗是否也可以预防常见的牙槽骨骨量减少 绝经后骨质疏松症患者。NELL-1是一种有效的促成骨和抗吸收蛋白， 最近发现对骨质疏松性骨丢失发挥全身性保护作用。的聚乙二醇化 NELL-1（NELL-PEG）作为全身治疗增强了NELL-1的药代动力学。因此，初步 研究表明，全身性NELL-PEG再生卵巢切除术诱导的骨丢失不仅在长期， 骨，而且在小鼠的上颌骨牙槽骨中。这导致了我们的中心假设， NELL-PEG治疗可以逆转颅后（骨外和轴向）和 颅面（颅骨、上颌骨和下颌骨）骨骼。我们将在三个具体目标中检验这一假设： AIM 1.测定NELL-1和PEG化的NELL-1的药代动力学和靶向效率 NELL-1。为此，我们将确定全身NELL-PEG在骨和血浆中的药代动力学特征 在8周的时间里。将分析颅后骨和颅面骨。 AIM 2.确定PEG化的NELL-1在再生颌骨中的治疗效果 与后颅骨一起被发现。AIM 2A将评价全身NELL-PEG的作用 对OVX诱导的骨质疏松小鼠的颅面骨与颅后骨的影响。先前确定 将测试全身性NELL-PEG制剂，并评估骨密度、形成和转换。 同时，AIM 2B将评估NELL-PEG对干细胞数量和活性的全身影响， 下颌骨、长骨和椎骨中的成骨细胞（OB）和破骨细胞（OC）。 AIM 3.检查Nell-1对颅面与颅后骨骼发育的影响， 在成骨细胞特异性转基因敲除小鼠中的维持。为此，我们将于近期 用2.3kbCol1-Cre和Wnt 1-Cre构建Nell-1flox/flox小鼠，检测成骨细胞和神经嵴特异性 效果分别。 新的基于rNELL-1的疗法可以极大地提高骨质疏松症治疗的护理标准， 牙齿骨质减少及其发病率。开发一种可以促进双重合成代谢和 在颅面骨和颅后骨中的抗骨坏死作用将提供一种开创性的治疗方法。