Mesenchymal Regulation of Jaw Bone Length

颌骨长度的间充质调节

• 批准号: 8090949
• 负责人: Erin Ealba Bumann
• 金额: $ 12.51万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090949
• 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' 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; repaired; research study; skeletal; skills; treatment strategy

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）：这是一份为Erin Ealba博士申请K08奖的申请，她是加州大学旧金山分校的一名普通牙医。Ealba博士是颅面骨发育基础科学研究领域的一名年轻研究者。K08奖将为Ealba博士提供必要的支持，以实现以下目标：(1)成为发育、骨骼和颅面生物学的专家；(2)注重教师技能；(3)提高她的稿件和论文写作能力。为了实现这些目标，Ealba博士组建了一个指导团队，由一位主要导师Richard Schneider博士（颅面发育领域的权威）、两位共同导师Pamela DenBesten博士（专注于牙釉质矿化的领先牙科科学家）和Tamara Alliston博士(TGF？以及三位合作者（Mary Nakamura博士、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的长度和形状，作为解决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质（NCM）如何调节颌骨大小来实现这一目标，神经嵴间质构成了面部和颌骨骨骼的所有元素。为了解决这个问题，我们在体内操纵NCM，一个高度可接近的胚胎群体。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，从而产生嵌合鸭；我们将较慢的鸭子供体NCM移植到相对较快的鹌鹑宿主体内，产生嵌合的双尾鸭。利用鹌鹑和鸭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依赖的过程。此外，所有的鹌鹑细胞都可以通过一种无处不在的核标记来检测，而这种标记在鸭子中并不存在。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起关键作用，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？信号，NCM指导自己的成骨程序和协调破骨细胞的活动来控制颌骨长度。为了验证我们的假设，我们提出了三个互补且不相互依存的具体目标。特异性目标1将确定NCM使用TGF2信号控制下颌长度的程度。特异性目标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。特异性Aim 3将确定NCM通过tgf2依赖性RANKL/OPG信号影响破骨细胞活性和颌骨长度的程度。我们将采用功能增益和功能损失技术来确定赋予NCM控制颚长能力的分子机制。从这个提议的实验可以作为一个原则的证明，分子为基础的疗法可以设计来治疗疾病，影响下巴的长度。此外，确定供体NCM对宿主细胞（如破骨细胞）影响的传导机制，对创伤或骨质疏松症和骨坏死等疾病损伤的骨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提供基础，以治疗各种临床骨骼疾病。