Novel systemic PEGylated NELL-1 therapy for craniofacial osteoporosis

项目摘要/摘要 一、候选人 我是一名获得董事会认证的正畸医生，也是加州大学洛杉矶分校牙科学院的研究跟踪教员。我是双重身份- 训练有素的临床科学家，拥有丰富的骨组织工程背景，发表了16篇论文，24篇 领奖台上发表了摘要演讲，并获得了6项国家级优秀研究奖项。在过去的7年中 多年来，我在加州大学洛杉矶分校与各种跨学科研究团队广泛合作，在此基础上，我 寻求谢家秀博士的初级指导，并成立了本届 求婚。在苏博士的新指导下，我正在建立一种明确的独立于我的 前任和现任导师的工作，证明了我在当前提案中描述的最近的成就。 我目前的职业目标是争取时间和精力通过K08进行研究和职业发展 奖励，继续设计与国家研究需求相关的创新，并在我多产的基础上 发布记录。我的最终目标是在终身教员的职位上实现科学独立，并继续 通过跨学科的努力满足国家的生物医学和临床研究需求。K08奖将会 通过提供(I)培养多学科的结构化计划，对我的职业发展大有裨益 研究技能，(Ii)工资支持，以保持对研究跟踪的承诺，和(Iii)受保护的研究时间。 为这项提案而成立的令人震惊的五人咨询委员会由发展和 分子生物学家、具有FDA经验的临床科学家和生物工程师提供这方面的指导 高度翻译性和多学科项目。杰出而经验丰富的导师由以下人员组成 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。 除了得到牙科学院的一致机构支持外，我还将受益于 加强我的导师和他们的研究合作者之间存在的强大合作。 二、环境问题 加州大学洛杉矶分校是世界领先的公共研究机构之一，为 拥有丰富的智力资源、丰富的研究设施和强大的制度支持的环境。这个 加州大学洛杉矶分校的制度环境提供了大量紧密结合和共享的物质和人类 能够促进年轻科研人员成长和智力发展的资源。 三、调研 牙齿骨量减少及其相关疾病，如牙齿脱落、牙周种植失败和适合性不良 预计到2040年，全球假牙成本将超过2400亿美元。骨质疏松症的治疗方法 骨丢失主要集中在合成代谢药或抗吸收药上。然而，迫切需要 开发既针对骨形成又针对吸收的新制剂。重要的是，没有确凿的证据 这支持了骨质疏松疗法是否也能预防常见的牙槽骨质疏松症 绝经后骨质疏松症患者。Nell-1是一种强大的促成骨和抗吸收蛋白， 最近被发现对骨质疏松性骨丢失具有系统的保护作用。聚乙二醇化 作为一种全身治疗，NEL-1(NEL-PEGO)促进了NEL-1‘S的药代动力学。因此，初步的 研究表明，全身性Nell-PEG不仅能再生卵巢切除所致的骨丢失 骨，也存在于小鼠上颌骨的牙槽骨中。这导致了我们的核心假设，即系统性 Nell-PEG治疗可逆转颅后(附件和枢椎)骨质疏松性骨丢失 头面部(头盖骨、上颌骨和下颌骨)的骨骼。我们将从三个具体目标来检验这一假设： 目的1.测定Nell-1和PEGylated的药代动力学和靶向性 内尔-1。为了达到这个目的，我们将测定全身性的耐尔-聚乙二醇在骨骼和血浆中的药代动力学。 在8周的时间里。将对后颅骨和颅面部骨骼进行分析。 目的2.测定聚乙二醇化Nell-1对颌骨再生的治疗效果 在骨质疏松小鼠的颅后骨旁。Aim 2A将评估全身性Nell-PEG的效果 OVX诱导的骨质疏松症小鼠的颅面骨与颅后骨。先前确定的 将测试全身Nell-PEG的配方，并评估骨密度、形成和转换率。 同时，AIM 2B将评估系统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)。 目的3.研究Nell-1对颅面部和颅后骨骼发育的影响 成骨细胞特异性转基因基因敲除小鼠的维持。在这个目标下，我们将跨越我们最近的 用2.3kb的col1-Cre和Wnt1-Cre建立Nell-1 FLOX/FLOX小鼠，以检测成骨细胞和神经脊的特异性 效果分别为。 基于RNELL-1的新疗法可以极大地提高治疗骨质疏松症的护理标准， 牙科骨质疏松症及其发病率。一种系统疗法的发展，可以促进双重合成代谢和 在颅面骨和颅后骨中的抗破骨作用将提供一种开创性的治疗方法。

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.