GENETIC DETERMINATION OF SKELETAL FRAGILITY

描述(申请人提供)：该项目的长期目标是更好地了解骨骼脆性的遗传基础。具体地说，这些研究旨在确定i)多个遗传基因如何相互作用来调节骨骼的形态和质量，以及ii)这些关键的中介特征如何决定定义组织骨折易感性的整个骨骼机械特性。 这项建议的目的是确定遗传背景如何调节有助于整个骨骼机械功能的中间骨特征(形态、质量)。主要结果是在发育过程中细胞活动指标(即基质形成、吸收、矿化的模式)的一致性，这些指标导致与机械相关的骨骼特征的遗传变异。这些生物过程在时间上先于时间，因此，预计对成人骨骼的形状和质量是决定性的。工作假设是，指定骨骼形态和质量的特征是相互依赖和协调调节的。由于复杂的中间性状是多个基因共同作用的结果，因此将利用来自AJ和B6小鼠的重组近交系(RI)小鼠品系进行分析。在RI品系组中，通过测量亲本基因组遗传随机化后性状共分离的趋势，将建立中间骨骼性状之间的功能相互作用网络。利用这一新的系统方法，将根据结构层次和年龄构建描述细胞指数和与脆弱性相关的属性之间功能相互作用的网络，首先针对女性(目标1)，然后针对男性(目标2)。然后，我们将测试已识别的层级特征的机械控制是否在不同的基因型之间共享(目标3)。 这些研究的成功完成将确定决定性的细胞指数，这些指数可在未来的研究中用作表型标记，以确定相关的遗传位点。这些标记提供的优势是，遗传位点将与关键的生物过程密切相关。此外，网络分析将揭示这些基因最终是如何与与脆性相关的复杂的全骨特性相关的。这些功能相互作用对于开发全面的骨骼系统分析至关重要，这将为骨质疏松的早期诊断和预防性治疗产生基于遗传的策略。

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand better the genetic basis of skeletal fragility. In particular, these studies aim to determine i) how multiple genetic loci interact to regulate bone morphology and quality, and ii) how those critical intermediary traits determine the whole bone mechanical properties that define the tissue's susceptibility to fracture. The goal of this proposal is to determine how genetic background regulates the intermediary bone traits (morphology, quality) that contribute to whole bone mechanical function. The principal outcome is the identities of indices of cellular activity (i.e. patterns of matrix formation, resorption, mineralization) occurring during development that give rise to genetic variation in mechanically relevant bone traits. These biological processes precede temporally and are, thus, expected to be deterministic of adult bone shape and quality. The working hypothesis is that traits specifying bone morphology and quality are interdependent and coordinately regulated. Because complex intermediary traits result from the actions of multiple genes, Recombinant Inbred (RI) mouse strains derived from AJ and B6 mice will be utilized to facilitate analysis. Networks of functional interactions among intermediary skeletal traits will be established by measuring the tendency for traits to cosegregate after genetic randomization of the parental genomes in the RI strain panel. Using this novel systems approach, networks describing functional interactions between cellular indices and properties related to fragility will be constructed in relation to structural hierarchy and age, first for females (Aim 1) and then for males (Aim 2). We will then test whether the identified mechanistic controls of hierarchical traits are shared across genotypes (Aim 3). Successful completion of these studies will identify determinant cellular indices that can be used in future studies as phenotypic markers to identify relevant genetic loci. These markers offer the advantage that genetic loci will be closely associated with critical biological processes. Further, the network analysis will reveal how these genes are ultimately related to complex whole bone properties related to fragility. These functional interactions are critically important for developing a comprehensive systems analysis of bone that will generate genetic-based strategies for early diagnosis and prophylactic treatment of osteoporosis.