Mesenchymal Regulation of Jaw Bone Length

颌骨长度的间充质调节

• 批准号: 8713247
• 负责人: Erin Ealba Bumann
• 金额: $ 12.99万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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/8713247
• 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; public health relevance; 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.

描述（由申请人提供）：这是加利福尼亚大学旧金山分校的普通牙医Erin Ealba博士的K08奖。 Ealba博士正在建立自己的颅面骨发展基础科学研究的年轻研究者。该K08奖将为EALBA博士提供实现以下目标所需的支持：（1）成为发育，骨骼和颅面生物学专家； （2）专注于教师技能； （3）增强她的手稿和授予写作能力。为了实现这些目标，Ealba博士组建了一个由主要导师组成的指导团队[博士理查德·施耐德（Richard Schneider），《颅面发展领域的权威]，两位联合官员[博士帕梅拉·丹伯斯顿（Pamela Denbesten）是一位专注于搪瓷矿化的领先牙医科学家，而TGF专家塔玛拉·阿里斯顿（Tamara Alliston）博士？信号]和三个合作者[博士Mary Nakamura，Ralph Marcucio博士和Ophir Klein博士]。 Ealba博士的长期目标是发现基于分子的新型疗法，以调节骨骼的长度和形状，以此来解决颅面畸形的非手术治疗的需求。当前研究的目的是通过了解如何形成面部和下颌骨骼中所有元素的神经rest间充质（NCM）来朝着这一目标建立。为了解决这个问题，我们在体内操纵NCM，这是一个高度可访问的胚胎人群。具体而言，我们更快地将鹌鹑供体NCM移植到了较慢的鸭子宿主中，该鸭子的宿主会产生嵌合Quck。我们将较慢的鸭子供体NCM移植到相对更快的鹌鹑宿主中，从而产生嵌合duail。利用鹌鹑和鸭的发散发展程序提供了一种独特的方法来操纵NCM和相邻宿主组织之间的信号传导，并允许发现NCM依赖性过程。同样，可以通过鸭中不存在的普遍存在的核标记来检测所有鹌鹑细胞。在已发表的工作和初步研究中，我们观察到NCM自主同步并指导成骨诱导，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，这是未知的。可能的候选者可能包括转化生长因子-Beta（TGF2）的成员和靶标，因为已知它们在成骨过程中起着关键作用，并且它们的表达在嵌合体中发生了改变。因此，我们通过调节TGF水平来假设这一点？信号传导，NCM指导其自己的成骨程序，并协调破骨细胞的活性以控制下颌长度。为了检验我们的假设，我们提出了三个互补和非依赖性特定目的。特定的目标1将确定NCM采用TGF2信号来控制下颌长度的程度。具体目标2将确定NCM依赖于破骨细胞调节颌骨长度的作用的程度。特定的目标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。我们将采用功能丧失技术来识别赋予NCM控制下颌长度的分子机制。该提案的实验可以作为原则上的证明，即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，识别供体NCM对宿主细胞（例如骨细胞）的影响的机制对因创伤或骨质疏松和骨质症（如骨质疏松症）造成的骨骼的修复和再生具有影响。我们希望我们的研究能为基于生物学的非手术方法提供基础，以纠正各种临床骨骼状况。