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.

项目摘要 /摘要 I.候选人 我是UCLA牙科学院的董事会认证的牙齿矫正医生和研究轨道。我是双重的 受过训练的临床医生科学家，具有16个出版物的骨组织工程背景，24 迄今为止，讲台摘要演示和6个国家级卓越研究奖。过去7 多年以来，我已经与加州大学洛杉矶分校的各种跨学科研究团队合作，根据我 寻求Chia Soo博士的主要指导，并成立了当前的五人咨询委员会 提议。在Soo博士的新指导下，我正处于与我的明确独立性的道路上 我最近的成就在当前的提案中描述了以前的和当前的导师的工作。 我的直接职业目标是通过K08确保时间和精力为研究职业发展 奖励，继续设计与国家研究需求相关的创新，并以我的多产为基础 出版记录。我的最终目标是使科学独立在任职教师职位上，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。 K08奖将 通过提供（i）培养多学科的结构化计划，从而使我的职业发展受益匪浅 研究技能，（ii）维持对研究轨道承诺的工资支持，以及（iii）受保护的研究时间。 为此提案组成的惊人五人咨询委员会包括发展和 分子生物学家，具有FDA经验的临床医生以及在此提供指导的生物工程师 高度翻译和多学科项目。杰出和经验丰富的导师由 UCLA研究社区的领先成员，并将提供研究和行政支持。 除了从牙科学院获得一致的机构支持外，我还将受益于 加强我的导师与他们的研究合作者之间存在的强大合作。 ii。环境 加州大学洛杉矶分校是世界上领先的公共研究机构之一，并提供了出色的学术 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环境。这 加州大学洛杉矶分校的机构环境提供了大量紧密整合和共享的物理和人类 可以促进年轻科学研究者的成长和智力发展的资源。 iii。研究 牙齿骨质减少症及其相关的病因，例如牙齿脱落，牙周植入物失败和不适 牙齿预计到2040年将在全球范围内耗资超过2400亿美元。骨质疏松的治疗方法 骨质流失集中在合成代谢或抗吸收剂上。但是，迫切需要 开发针对骨形成和吸收的新药物。重要的是，没有具体的证据 这支持骨质疏松疗法是否也可以防止经常看到的牙道肺泡减少症 在绝经后骨质疏松患者中。 NELL-1是一种有效的促稳态和抗敏感性蛋白 最近发现，针对骨质疏松骨质流失具有系统性的保护功能。 Pegylation NELL-1（Nell-Peg）已将Nell-1的药代动力学作为一种全身疗法增强。结果，初步 研究表明，全身Nell-Peg再生卵巢切除术引起的骨质流失，不仅在长时间内 骨骼，但在小鼠的上颌牙槽骨中也是。这导致了我们的核心假设 Nell-Peg疗法可以逆转颅后（阑尾和轴向）和 颅面（颅骨，上颌骨和下颌骨）骨骼。我们将以三个具体的目的检验这一假设： 目标1。确定NELL-1的药代动力学和靶向效率 内尔1。在此目标中，我们将确定骨骼和等离子体中系统性Nell-Peg的药代动力学特征 在8周的时间内。将分析颅后和颅面骨骼。 AIM 2。确定Pegypated Nell-1在再生下颌骨骼中的治疗功效 与骨质疏松小鼠中的颅后骨骼一起。 AIM 2A将评估全身Nell-Peg的效果 在OVX诱导的骨质疏松小鼠中，在颅面与颅后骨骼上。先前确定 将测试全身性Nell-Peg的配方，将评估骨密度，形成和周转率。 同时，AIM 2B将评估全身Nell-Peg对干细胞数量和活性的影响， 下颌骨，长骨和椎骨中的成骨细胞（OB）和破骨细胞（OC）。 目标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维持。在这个目标中，我们将越过我们的最近 用2.3kb col1-cre和Wnt1-cre生成的Nell-1flox/Flox小鼠检查成骨细胞和神经crest特异性 效果分别。 新型基于RNELL-1的疗法可以极大地改善骨质疏松症治疗的护理标准， 牙齿骨质减少症及其病态。开发可以促进双重合成代谢和的全身疗法 颅面和颅后骨骼中的抗骨碎屑作用将提供开创性的疗法。