Temporal balance between Notch and Wnt signaling during fracture healing

骨折愈合过程中 Notch 和 Wnt 信号传导的时间平衡

• 批准号: 9895632
• 负责人: Philipp Leucht
• 金额: $ 18.06万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895632
• 关键词: Adult; Advisory Committees; Aging; Algorithms; Antibodies; Attention; Basic Science; Biology; Biomimetics; Bone Marrow; Bone Regeneration; Bone callus; Cell Count; Cell Differentiation process; Cell Fate Control; Cell Proliferation; Cells; Chimeric Proteins; Choices and Control; Degenerative Disorder; Development; Development Plans; Disease; Embryonic Development; Equilibrium; Expression Profiling; Fracture; Fracture Healing; Funding; Future; GTP-Binding Protein alpha Subunits, Gs; Goals; Growth; Growth Factor; Harvest; Homeostasis; Human body; Impairment; Injury; Investigation; Knowledge; Link; Maps; Mentors; Mentorship; Molecular; Muscle; Natural regeneration; Notch Signaling Pathway; Notch and Wnt Signaling Pathway; Organ; Orthopedics; Pathway interactions; Patients; Periosteum; Phase; Play; Population; Positioning Attribute; Process; Proteins; Research; Research Personnel; Research Proposals; Role; Scientist; Shapes; Signal Pathway; Signal Transduction; Site; Somatotropin; Speed; Sum; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; WNT Signaling Pathway; adult stem cell; bone; bone healing; career; career development; clinically relevant; experimental study; functional restoration; gamma secretase; healing; in vivo; in vivo regeneration; inhibitor/antagonist; insight; jagged1 protein; member; notch protein; osteoblast differentiation; osteogenic; osteoprogenitor cell; programs; public health relevance; regenerative; repaired; research and development; response to injury; self-renewal; skeletal; skeletal injury; skills; stem cell biology; stem cell proliferation; stem cells; targeted treatment; therapeutic target; therapy development; tissue regeneration

 DESCRIPTION (provided by applicant): The field of stem cell biology is advancing at an incredible speed, with new techniques emerging on a regular basis allowing for deeper investigations into the mechanisms underlying adult stem cell biology and tissue regeneration. Wnt signaling and Notch signaling have been identified as two key pathways that regulate adult stem cell proliferation and differentiation. Past research has focused on the role of Wnt signaling during bone regeneration, in particular on its role as a stem cell activator and pro-osteogenic growth factor. The Notch signaling pathway, however, has not received much attention, even though there is good evidence in embryonic development and adult tissue regeneration (i.e. muscle) that the Notch signaling pathway plays a central role in progenitor cell proliferation. In this proposal, we will focus on the Notch and Wnt signaling pathway, in particular how the two pathways orchestrate early stem cell proliferation and differentiation. (1) We will first characterize the Notch and Wnt responsiveness of osteoprogenitor cells within the injury site and map the spatial and temporal expression profile of members of both pathways. (2) We will then inhibit Notch signaling during the early proliferative phase, which will identify the degree t which Notch signaling regulates proliferation and potentially influences subsequent differentiation. (3) In the last aim, we will independently activate Notch and Wnt signaling in viv to define the potential coordinate activity between the two pathways during adult bone stem cells activation. While much effort has been exerted into identifying the effect of a singular growth hormone on bone regeneration, our research seeks to characterize a well-orchestrated interplay between two well-known pathways. This proposal may expose potential therapeutic targets, which may result in the future development of biomimetic treatment algorithms with the goal of enhancing the body's own regenerative capacity. My career goal is to conduct clinically relevant basic research as an orthopaedic clinician scientist. This career development plan and research proposal will allow me to focus my efforts on acquiring the desired skills that are necessary to become a successful clinician scientist. Receiving mentorship from my two highly accomplished primary mentors in addition to the five members of my advisory committee will guarantee my gradual growth into a competitive researcher in the field of bone biology. This expected academic growth in addition to the acquired new skills sets will place me in a prime position to compete for independent R01 funding.

 描述(申请人提供)：干细胞生物学领域正在以令人难以置信的速度前进，定期出现的新技术允许对成人干细胞生物学和组织再生的潜在机制进行更深入的研究。WNT信号和Notch信号被认为是调节成体干细胞增殖和分化的两条关键途径。过去的研究主要集中在Wnt信号的作用上 在骨再生过程中，特别是其作为干细胞激活剂和促成骨生长因子的作用。然而，尽管在胚胎发育和成人组织再生(如肌肉)中有很好的证据表明Notch信号通路在祖细胞增殖中起核心作用，但Notch信号通路仍未受到太多关注。在这个提案中，我们将重点介绍Notch和Wnt信号通路，特别是这两个通路如何协调早期干细胞的增殖和分化。(1)我们将首先描述损伤部位骨祖细胞对Notch和Wnt的反应性，并绘制这两条通路成员的空间和时间表达图谱。(2)我们将在增殖早期抑制Notch信号，这将确定Notch信号调节增殖的程度，并可能影响随后的分化。(3)在最后一个目标中，我们将独立地激活Viv中的Notch和Wnt信号，以确定在成人骨干细胞激活过程中这两条信号通路之间的潜在协同活性。虽然人们已经做出了很多努力来确定单一生长激素对骨再生的影响，但我们的研究试图描述两条众所周知的途径之间精心安排的相互作用。这一提议可能会暴露潜在的治疗靶点，这可能会导致未来仿生治疗算法的发展，目标是增强人体自身的再生能力。我的职业目标是作为一名骨科临床科学家进行与临床相关的基础研究。这份职业发展计划和研究计划将使我能够集中精力获得成为一名成功的临床科学家所必需的所需技能。除了我的顾问委员会的五名成员外，得到我的两位非常有成就的初级导师的指导将确保我逐步成长为骨生物学领域的一名有竞争力的研究人员。这种预期的学术增长，加上获得的新技能，将使我处于竞争独立R01资金的首要地位。

项目成果

Temporary inhibition of the plasminogen activator inhibits periosteal chondrogenesis and promotes periosteal osteogenesis during appendicular bone fracture healing.

• DOI: 10.1016/j.bone.2018.04.016
• 发表时间: 2018-07
• 期刊: Bone
• 影响因子: 4.1
• 作者: Bravo D;Josephson AM;Bradaschia-Correa V;Wong MZ;Yim NL;Neibart SS;Lee SN;Huo J;Coughlin T;Mizrahi MM;Leucht P
• 通讯作者: Leucht P