Mesenchymal Regulation of Jaw Bone Length

颌骨长度的间充质调节

基本信息

批准号：
8238334
负责人：
Erin Ealba Bumann
金额：
$ 9.97万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8238334
关键词：
Accounting Address Adolescent Affect Anatomy Award Basic Science Beak Biological Assay Biology Birds Bone Development Bone Regeneration Bone necrosis California Candidate Disease Gene Cells Chimera organism Clinical Complex Congenital Abnormality Data Dental Enamel Dentists Deposition Development Disease Ducks Dysplasia Embryo Event Exhibits Face Faculty Family Foundations Gelatinase A Genes Goals Grant Human Hyperplasia Indium Injury Jaw Length Loeys-Dietz Syndrome Manuscripts Mentors Mesenchymal Mesenchyme Methods Micrognathism Molecular Mus Mutate Mutation Natural regeneration Neural Crest Nuclear Operative Surgical Procedures Osteoblasts Osteoclasts Osteogenesis Osteoporosis Paget&apos s Disease Pathway interactions Play Population Process Publishing Quail Regulation Research Research Personnel Role San Francisco Scientist Shapes Signal Transduction Skeleton Specific qualifier value Staging Syndrome System TGF-beta type I receptor TNFSF11 gene Techniques Testing Time Tissues Transforming Growth Factor beta Transplantation Trauma Tumor necrosis factor receptor 11b Universities Work Writing authority base bone craniofacial design in vivo injured loss of function malformation member mineralization novel osteogenic prevent programs public health relevance repaired research study skeletal skills treatment strategy

项目摘要

DESCRIPTION (provided by applicant): This is an application for a K08 award for Dr. Erin Ealba, a general dentist at the University of California, San Francisco. Dr. Ealba is establishing herself as a young investigator in basic science research of craniofacial bone development. This K08 award will provide Dr. Ealba with the support necessary to accomplish the following goals: (1) to become an expert in developmental, skeletal, and craniofacial biology; (2) to focus on faculty skills; and (3) to enhance her manuscript and grant writing abilities. To achieve these goals, Dr. Ealba has assembled a mentoring team comprised of a primary mentor [Dr. Richard Schneider, an authority in the field of craniofacial development], two co-mentors [Dr. Pamela DenBesten, a leading dentist-scientist focused on enamel mineralization, and Dr. Tamara Alliston, an expert in TGF? signaling], and three collaborators [Dr. Mary Nakamura, Dr. Ralph Marcucio, and Dr. Ophir Klein]. Dr. Ealba's long-term goal is to discover novel molecular-based therapies for regulating the length and shape of bone as a means to address the need for non-surgical treatments of craniofacial malformations. The objective of the current study is to build toward this goal by understanding how neural crest mesenchyme (NCM), which forms all the elements in the facial and jaw skeletons, regulates jaw size. To address this issue, we manipulate in vivo the NCM, a highly accessible embryonic population. Specifically, we transplant faster- maturing quail donor NCM into a slower-developing duck host, which creates chimeric quck; and we transplant slower duck donor NCM into the relatively faster quail host, generating chimeric duail. Exploiting the divergent developmental programs of quail and duck provides a unique way to manipulate signaling between NCM and adjacent host tissues, and allows discovery of NCM-dependent processes. Also, all quail cells can be detected via a ubiquitous nuclear marker not present in duck. In published work and in preliminary studies, we observe that NCM autonomously synchronizes and directs osteogenic induction, proliferation, differentiation, matrix deposition, mineralization, and matrix remodeling. How NCM accomplishes such a complex task, and what factors are sufficient to replicate this phenomenon, is unknown. Likely candidates may include members and targets of the Transforming Growth Factor-Beta (TGF2) since they are known to play critical roles during osteogenesis, and their expression is altered in chimeras. Therefore, we hypothesize that by modulating levels of TGF? signaling, NCM directs its own osteogenic program and coordinates the activities of osteoclasts to control jaw length. To test our hypothesis, we propose three complementary and non-interdependent Specific Aims. Specific Aim 1 will determine the extent to which NCM employs TGF2 signaling to control jaw length. Specific Aim 2 will determine the extent to which NCM relies on the actions of osteoclasts to regulate jaw length. Specific Aim 3 will determine the extent to which NCM acts via TGF2-dependent RANKL/OPG signaling to affect osteoclast activity and jaw length. We will employ gain- and loss-of-function techniques to identify molecular mechanisms that endow NCM with the ability to control jaw length. Experiments from this proposal can serve as a proof-of-principle that molecular-based therapies can be devised to treat disorders that affect the length of the jaw. Moreover, identifying mechanisms through which donor NCM transduces its effects on host cells such as osteoclasts has implications for repair and regeneration of bones injured by trauma or diseases like osteoporosis and osteonecrosis. We are hopeful that our research will provide a foundation for biologically based, non-surgical methods to remedy a variety of clinical skeletal conditions. PUBLIC HEALTH RELEVANCE: What controls the length of bone? Answering this question is important for preventing and treating birth defects, as well as for devising new therapies to repair or regenerate bones affected by injury or disease. The goal of this project is to identify genes and embryonic events that determine jaw length.

描述（由申请人提供）：这是加州大学旧金山分校普通牙医 Erin Ealba 博士的 K08 奖项申请。 Ealba 博士正在将自己定位为颅面骨发育基础科学研究的年轻研究者。 K08 奖项将为 Ealba 博士提供实现以下目标所需的支持：（1）成为发育、骨骼和颅面生物学方面的专家；（二）注重师资力量； (3) 提高她的手稿并提高写作能力。为了实现这些目标，Ealba 博士组建了一个由主要导师 [Dr.理查德·施奈德 (Richard Schneider)，颅面发育领域的权威]，两位共同导师 [Dr. Pamela DenBesten 是一位专注于牙釉质矿化的顶尖牙医科学家，Tamara Alliston 博士是 TGF? 专家。信号]和三位合作者[博士。 Mary Nakamura、Ralph Marcucio 博士和 Ophir Klein 博士]。 Ealba 博士的长期目标是发现新的基于分子的疗法来调节骨骼的长度和形状，作为满足颅面畸形非手术治疗需求的一种手段。当前研究的目的是通过了解神经嵴间充质（NCM）（形成面部和下颌骨骼的所有元素）如何调节下颌尺寸来实现这一目标。为了解决这个问题，我们在体内操纵 NCM，这是一种易于接近的胚胎群体。具体来说，我们将成熟较快的鹌鹑供体 NCM 移植到发育较慢的鸭宿主中，从而产生嵌合鹌鹑；我们将较慢的鸭供体 NCM 移植到相对较快的鹌鹑宿主中，产生嵌合双体。利用鹌鹑和鸭子不同的发育程序提供了一种独特的方法来操纵 NCM 和邻近宿主组织之间的信号传导，并允许发现 NCM 依赖性过程。此外，所有鹌鹑细胞都可以通过鸭子中不存在的普遍存在的核标记来检测。在已发表的工作和初步研究中，我们观察到 NCM 自主同步和指导成骨诱导、增殖、分化、基质沉积、矿化和基质重塑。 NCM 如何完成如此复杂的任务，以及哪些因素足以复制这种现象，目前尚不清楚。可能的候选者可能包括转化生长因子-β (TGF2) 的成员和靶标，因为已知它们在成骨过程中发挥关键作用，并且它们的表达在嵌合体中发生改变。因此，我们假设通过调节 TGF 的水平？通过信号传导，NCM 指导其自身的成骨程序并协调破骨细胞的活动以控制下颌长度。为了检验我们的假设，我们提出了三个互补且不相互依赖的具体目标。具体目标 1 将确定 NCM 利用 TGF2 信号传导来控制下颌长度的程度。具体目标 2 将确定 NCM 在多大程度上依赖破骨细胞的作用来调节下颌长度。具体目标 3 将确定 NCM 通过 TGF2 依赖性 RANKL/OPG 信号传导影响破骨细胞活性和下颌长度的程度。我们将采用功能获得和丧失技术来确定赋予 NCM 控制下颌长度能力的分子机制。该提案的实验可以作为原理证明，证明可以设计基于分子的疗法来治疗影响下巴长度的疾病。此外，确定供体 NCM 将其作用转变成破骨细胞等宿主细胞的机制，对于因创伤或骨质疏松症和骨坏死等疾病而损伤的骨骼的修复和再生具有重要意义。我们希望我们的研究将为基于生物学的非手术方法治疗各种临床骨骼疾病提供基础。公共卫生相关性：什么控制骨骼的长度？回答这个问题对于预防和治疗出生缺陷以及设计新疗法来修复或再生受损伤或疾病影响的骨骼非常重要。该项目的目标是识别决定下颌长度的基因和胚胎事件。