ARCHITECTURAL MICROFIBRILS IN BONE PHYSIOLOGY

骨生理学中的结构微纤维

• 批准号: 7900628
• 负责人: Francesco B Ramirez
• 金额: $ 9.49万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2010-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7900628
• 关键词: Abnormal Cell; Accounting; Affect; Applications Grants; Architecture; Basic Science; Biological; Biomechanics; Bone Regeneration; Bone remodeling; Candidate Disease Gene; Cartilage; Cell Culture Techniques; Cells; Clinical; Collagen; Defect; Development; Disease Progression; Drug Formulations; Elastic Fiber; Elastin; Equilibrium; Event; FBN1; Functional disorder; Funding; Genes; Genetic Variation; Goals; Growth; Growth and Development function; Hybrids; Image; Individual; Knockout Mice; Light; Maintenance; Marfan Syndrome; Microfibrils; Minerals; Modality; Mus; Mutant Strains Mice; Mutation; Nature; Osteogenesis; Osteoporosis; Patients; Performance; Periosteum; Physiology; Play; Polymers; Predisposing Factor; Process; Property; Proteins; Research Personnel; Rest; Role; Signal Transduction; Signaling Molecule; Skeleton; Stem cells; Testing; Tissues; base; body system; bone; bone loss; bone mass; bone strength; clavicle; design; effective therapy; evidence base; extracellular; fetal; fibrillin; fibrillin-2; genetic profiling; improved; innovation; novel; osteoporosis with pathological fracture; postnatal; programs; research study; response; scaffold; skeletal; skeletal tissue; spatiotemporal

DESCRIPTION (provided by applicant): We seek to understand the contribution of extracellular microfibrils to bone physiology and implicitly, to elucidate the pathological underpinning of skeletal manifestations in Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA). MFS and CCA are respectively caused by mutations in fibrillins 1 and 2, the major structural components of microfibrils. Extracellular microfibrils, alone or in association with elastin as elastic fibers, constitute the architectural scaffold of multiple organ systems, including the skeleton. Progress during the past funding cycle has revealed that disease progression in fibrillinopathies is accounted for in part by loss of tissue integrity and in part by dysregulated signaling events and abnormal cell performance. Preliminary studies suggest that fibrillin-1 and fibrillin-2 deficiencies affect bone formation and resorption to different extents by altering the balance of local signals that control maintenance of bone mass. We therefore hypothesize that a causal relationship exists in the skeleton between the extent of the microfibril defect and the levels of dysregulated signaling and cellular responses. By analogy to the consequences of collagen I mutations on bone function, we also postulate that fibrillin mutations may negatively impact on the ability of these components of the architectural matrix to confer material and structural properties to skeletal tissue. The premise of the present application therefore rests on the innovative, evidence-based hypothesis that architectural microfibrils play two distinct roles in bone physiology - the role of regulators of signaling molecules to modulate bone formation, growth and turnover, and the role of a structural support for the matrix to impart bone strength. Accordingly, we propose to utilize fibrillin mutant mice to (a) characterize the identity and nature of the cellular defects responsible for reduced bone mass in mice underexpressing fibrillin-1 or lacking fibrillin-2; (b) elucidate the differential roles of fibrillins 1 and 2 in cortical bone formation; and (c) assess the impact of graded loss of fibrillin-rich microfibrils on matrix organization, material quality and biomechanical properties of bone and cartilage. The significance of the proposed studies is that an understanding of fibrillin function in the skeleton will shed new light on the ill-defined relationship between resident cells and the architectural matrix in this organ system. The long-term goal of this grant application is to generate basic science information that will benefit the design of rational therapies for bone mineral replacement in patients affected with Marfan syndrome, and which will improve our understanding of the nature of predisposing factors in osteoporosis.

描述（由申请人提供）：我们试图了解细胞外微原纤维对骨生理学的贡献，并隐含地阐明马凡综合征（MFS）和先天性挛缩性蜘蛛指畸形（CCA）骨骼表现的病理基础。 MFS 和 CCA 分别是由微纤维的主要结构成分原纤维蛋白 1 和 2 的突变引起的。细胞外微原纤维单独或与弹性蛋白结合作为弹性纤维，构成包括骨骼在内的多个器官系统的建筑支架。过去资助周期的进展表明，纤维蛋白病的疾病进展部分是由于组织完整性的丧失，部分是由于信号事件失调和细胞性能异常。初步研究表明，fibrillin-1 和 fibrillin-2 缺陷通过改变控制骨量维持的局部信号的平衡，在不同程度上影响骨形成和吸收。因此，我们假设骨骼中微原纤维缺陷的程度与失调的信号传导和细胞反应的水平之间存在因果关系。通过类比 I 型胶原突变对骨功能的影响，我们还假设原纤维蛋白突变可能会对建筑基质的这些成分赋予骨骼组织材料和结构特性的能力产生负面影响。因此，本申请的前提基于创新的、基于证据的假设，即结构微纤维在骨生理学中发挥两种不同的作用——信号分子调节剂调节骨形成、生长和更新的作用，以及结构支撑的作用为基质赋予骨强度。因此，我们建议利用原纤维蛋白突变小鼠来（a）表征原纤维蛋白-1表达不足或缺乏原纤维蛋白-2的小鼠中导致骨量减少的细胞缺陷的身份和性质； (b) 阐明原纤维蛋白 1 和 2 在皮质骨形成中的不同作用； (c) 评估富含原纤维蛋白的微原纤维的分级损失对骨和软骨的基质组织、材料质量和生物力学特性的影响。拟议研究的意义在于，对骨骼中原纤维蛋白功能的理解将为了解该器官系统中常驻细胞和结构基质之间的不明确关系提供新的线索。这项拨款申请的长期目标是产生基础科学信息，这将有利于为马凡综合征患者设计合理的骨矿物质替代疗法，并提高我们对骨质疏松症诱发因素性质的理解。

项目成果

Biogenesis and function of fibrillin assemblies.

• DOI: 10.1007/s00441-009-0822-x
• 发表时间: 2010-01
• 期刊: CELL AND TISSUE RESEARCH
• 影响因子: 3.6
• 作者: Ramirez, Francesco;Sakai, Lynn Y.
• 通讯作者: Sakai, Lynn Y.

Regulation of limb patterning by extracellular microfibrils.

• DOI: 10.1083/jcb.200105046
• 发表时间: 2001-07-23
• 期刊: The Journal of cell biology
• 作者: Arteaga-Solis E;Gayraud B;Lee SY;Shum L;Sakai L;Ramirez F
• 通讯作者: Ramirez F

Magnetic resonance microscopy quantifies the disease progression in Marfan syndrome mice.

磁共振显微镜定量马凡综合征小鼠的疾病进展。

• DOI: 10.1002/jmri.10279
• 发表时间: 2003
• 期刊: Journal of magnetic resonance imaging : JMRI.
• 作者: Itskovich,VitaliiV;Lieb,Mark;Aguinaldo,JuanGilbertoS;Samber,DanielD;Ramirez,Francesco;Fayad,ZahiA
• 通讯作者: Fayad,ZahiA

Extracellular microfibrils: contextual platforms for TGFbeta and BMP signaling.

• DOI: 10.1016/j.ceb.2009.05.005
• 发表时间: 2009-10
• 期刊: Current opinion in cell biology
• 影响因子: 7.5
• 作者: Ramirez F;Rifkin DB
• 通讯作者: Rifkin DB

Material and mechanical properties of bones deficient for fibrillin-1 or fibrillin-2 microfibrils.

• DOI: 10.1016/j.matbio.2011.03.004
• 发表时间: 2011-04
• 期刊: MATRIX BIOLOGY
• 影响因子: 6.9
• 作者: Arteaga-Solis, Emilio;Sui-Arteaga, Lee;Kim, Minwook;Schaffler, Mitchell B.;Jepsen, Karl J.;Pleshko, Nancy;Ramirez, Francesco
• 通讯作者: Ramirez, Francesco