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纤维对骨骼生理学的贡献，并隐含地阐明Marfan综合征（MFS）和先天性收缩性芳香族性的骨骼表现的病理基础（CCA）。 MFS和CCA分别是由原纤维1和2（微纤维的主要结构成分）突变引起的。单独或与弹性蛋白作为弹性纤维的细胞外微纤维构成了包括骨架在内的多个器官系统的建筑支架。在过去的融资周期中的进展表明，纤维蛋白病的疾病进展部分是由于组织完整性的丧失，部分原因是信号事件失调和细胞表现异常。初步研究表明，纤维蛋白-1和原纤维蛋白-2缺陷通过改变控制骨骼质量维持的局部信号的平衡来影响骨形成和吸收到不同的量表。因此，我们假设在微纤维缺陷程度与信号传导和细胞反应失调水平之间的骨骼中存在因果关系。类似于胶原I突变对骨功能的后果，我们还假设纤维蛋白突变可能会对建筑基质的这些成分赋予将物质和结构特性赋予骨骼组织的能力产生负面影响。因此，本应用的前提取决于创新的，基于证据的假设，即建筑微纤维在骨骼生理学中起了两个不同的作用 - 信号分子调节骨形成，生长和周转的作用，以及对基质的结构支撑的作用，以赋予骨骼强度。因此，我们建议利用原纤维蛋白突变小鼠（a）表征导致小鼠骨骼质量减少的细胞缺陷的身份和性质，使纤维素-1或缺乏纤维蛋白-2； （b）阐明原纤维蛋白1和2在皮质骨形成中的差异作用； （c）评估富含纤维蛋白的微纤维对基质组织，骨骼和软骨的材料质量和生物力学特性的分级损失的影响。拟议的研究的意义在于，对骨骼中纤维蛋白功能的理解将为居民细胞与该器官系统中的建筑基质之间的不确定关系提供新的启示。该赠款应用的长期目标是生成基础科学信息，以有利于受Marfan综合征影响的患者的骨矿物质替代的理性疗法的设计，这将提高我们对骨质疏松症倾向因素的性质的理解。

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