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Investigating Ultrastructural Collagen Changes in Osteogenesis Imperfecta

研究成骨不全症中胶原蛋白的超微结构变化

基本信息

批准号：
7663985
负责人：
Joseph Michael Wallace
金额：
$ 4.8万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7663985
关键词：
Affect American Architecture Atomic Force Microscopy Binding Biochemistry Biological Biological Models Biomedical Engineering Bone Diseases Bone Matrix Bone Tissue Carbon Cells Charge Chemicals Clinical Collagen Collagen Fibril Collagen Type I Communities Competence Connective Tissue Coupled Data Dendrimers Dentin Development Disease Doctor of Philosophy Drug or chemical Tissue Distribution Engineering Environment Excision Fracture Funding Goals Hereditary Disease Human Image In Situ In Vitro Investigation Joints Knock-in Mouse Knowledge Length Life Link Literature Measures Mechanics Methods Michigan Mission Modeling Modification Monitor Morphology Mus Mutation Nature Organism Osteogenesis Imperfecta Patients Physiology Polymers Predisposition Preparation Property Protein Binding Proteins Public Health Research Research Design Research Infrastructure Sampling Series Severities Skeleton Solid Structure Surface Tail Tendon structure Testing Tissues Translating Trauma Treatment Protocols United States Universities Width Wild Type Mouse Work base bone bone quality burden of illness density design disability innovation insight interdisciplinary approach mineralization physical property research study skeletal

项目摘要

DESCRIPTION (provided by applicant): The lack of understanding of how altered collagen structure in Osteogenesis Imperfecta (Ol) translates to insufficiencies in tissue integrity is a critical impediment to the implementation of treatment protocols designed to return bone properties to normal levels. The long-term goal is to understand how alterations in the bone ultrastructure in Ol influence higher level properties. The overall objective of this proposal is to relate [morphological changes] in Type I collagen fibrils from connective tissues of Ol mice [to fibril mechanical integrity and] the altered ability of proteins to bind to this collagen as measures of functional competence. The central hypothesis is that alterations in the [width, axial spacing and packing] of Ol Type I collagen fibrils will result in inappropriate organic matrix organization, [decreased fibril modulus] and [improper protein binding to diseased fibril] surfaces. The rationale for the proposed research is that once mechanical differences in Ol [tissues] can be linked to explicit changes in Type I collagen, appropriate treatment options can be developed to specifically target altered collagen functions. Therefore, this research is relevant to the NIH's mission to apply fundamental knowledge about the nature of living systems to extending healthy human life and reducing the burdens of illness and disability. Based on strong preliminary data and a solid literature base, the central hypothesis will be tested by pursuing two specific aims: 1) Identify morphological and organizational consequences of Ol in Type I collagen; and 2) Establish changes [in mechanical integrity and] in the ability of proteins to bind to Type I collagen in Ol as measures of functional competence. Atomic force microscopy coupled with dendritic polymers as model proteins will be used to probe the collagen of wild type, [Brtl/+] and [Brtl/Brtl] mice representing a [range] of Ol severity. Under the first aim, Type I collagen will be imaged in a variety of biological settings to determine how collagen physically [changes with mutation severity]. Under the second aim, physical differences in collagen will be correlated [with fibril modulus and] with alterations in the ability of proteins to bind to fibril surfaces as measures of functionality. The approach is innovative because it will begin linking architectural and functional aspects of Type I collagen at the ultrastructural level to higher-level properties in situ. As the United States is part of the current worldwide Bone and Joint Decade initiative, this research has clear relevance to public health. Uncovering the link between bone quality and structural integrity remains a key goal of the bone research community. Therefore, this research is not only applicable to Ol patients, but has broader implications for investigating other diseases related to ultrastructural modifications of bone.

描述（由申请人提供）：对成骨不全（OI）中胶原结构的改变如何转化为组织完整性的不稳定性缺乏了解，这是实施旨在将骨特性恢复到正常水平的治疗方案的关键障碍。长期的目标是了解骨超微结构的改变如何影响更高水平的性能。本提案的总体目标是将来自OI小鼠结缔组织的I型胶原原纤维中的[形态学变化]与[原纤维机械完整性和]蛋白质与该胶原结合的能力改变相关，作为功能能力的量度。中心假设是OI I型胶原原纤维的[宽度、轴向间距和堆积]的改变将导致不适当的有机基质组织、[原纤维模量降低]和[蛋白质与患病原纤维的不适当结合]表面。所提出的研究的基本原理是，一旦OI [组织]中的机械差异可以与I型胶原蛋白的明确变化联系起来，就可以开发适当的治疗方案来专门针对改变的胶原蛋白功能。因此，这项研究与美国国立卫生研究院的使命有关，即应用有关生命系统性质的基本知识来延长健康的人类寿命，减少疾病和残疾的负担。基于强有力的初步数据和坚实的文献基础，将通过追求两个特定目标来测试中心假设：1）鉴定I型胶原中OI的形态和组织后果;和2）建立蛋白质结合OI中I型胶原的能力的变化[机械完整性和]作为功能能力的量度。与作为模型蛋白的树枝状聚合物偶联的原子力显微镜将用于探测代表OI严重程度[范围]的野生型、[Brt 1/+]和[Brt 1/Brt 1]小鼠的胶原。在第一个目标下，I型胶原蛋白将在各种生物环境中成像，以确定胶原蛋白如何物理[随突变严重程度变化]。在第二个目标下，胶原蛋白的物理差异将与[原纤维模量和]蛋白质结合原纤维表面的能力的改变相关，作为功能性的量度。该方法是创新的，因为它将开始将I型胶原蛋白在超微结构水平上的结构和功能方面与原位更高水平的性质联系起来。由于美国是目前全球骨与关节十年倡议的一部分，这项研究与公共卫生有明显的相关性。揭示骨质量和结构完整性之间的联系仍然是骨研究界的一个关键目标。因此，本研究不仅适用于骨关节炎患者，而且对研究与骨超微结构改变相关的其他疾病具有更广泛的意义。