Genetic Determinants of Pathologic Heterogeneity in MS

描述(申请人提供)：我们的初步研究表明，在炎症的病理指标、主动脱髓鞘的主要免疫效应机制以及组织损伤和修复的程度方面，早期和慢性MS病变的个体内存在同质性。个体内病理同质性的证据可能反映了控制病变形成的基因座的遗传变异。我们建议收集大量MS病变样本并进行病理表型分析，以研究早期和慢性MS病变中炎症、脱髓鞘、再髓鞘形成和轴突损伤之间的复杂关系，并调查人口统计学和临床变量与这些病理结果的关系。此外，我们将评估这些明确定义的特定组织和免疫病理结果的个体内同质性程度，以验证我们对个体内同质性的初步观察，并更准确地确定可用于未来遗传学研究的每种病理表型的病例数量。我们的目标是建立一个可靠和统计可靠的MS组织DNA数据库，它将使用病理学作为未来遗传关联研究的新的中间结果。拟议的研究将产生大量具有详细和定量的病理分析和DNA的患者材料，并将提供一个框架，从发现基因组范围的连锁、群体关联和组织微阵列研究中感兴趣的染色体区域或候选基因，到详细的临床-病理分析，以确定致病相关性。通过根据特定的病理特征对患者进行分层，我们将增加识别每一类别共同的潜在基因贡献的可能性。此外，还有支持对多发性硬化症病理学和遗传学进行更多研究的实际原因。对MS病变演变中涉及的可变病理和遗传因素的更基本的了解不仅将为MS提供更多的病因学见解，而且将导致改善对长期预后的确定，以及影响针对患者量身定做的当前和未来治疗方法的选择和设计。

DESCRIPTION (provided by applicant): Our preliminary studies suggest there is intra-individual homogeneity within both early and chronic MS lesions with respect to pathologic measures of inflammation, dominant immune effector mechanisms of active demyelination, and extent of tissue injury and repair. Evidence of intra- individual pathological homogeneity may reflect genetic variation in loci controlling lesion formation. We propose to collect and pathologically phenotype a large sample of MS lesions in order to examine both the complex relationships between inflammation, demyelination, remyelination, and axonal injury in both early and chronic MS lesions, as well as investigate the relationship of demographic and clinical variables with these pathologic outcomes. In addition, we will assess the degree of intra-individual homogeneity for these well defined specific histo- and immunopathological outcomes in order to validate our preliminary observations of intra-individual homogeneity, and more accurately establish the number of cases within each of the respective pathological phenotypes available for future genetic study. We aim to establish a reliable and statistically robust MS Tissue-DNA Databank which will use pathology as a novel intermediate outcome for future genetic-association studies The proposed studies will yield a tremendous resource of patient material having both detailed and quantitative pathologic analyses and DNA, and will provide the framework for an efficient and cost-effective transition from discovery of chromosomal regions or candidate genes of interest in genome-wide linkage, population-association and tissue microarray studies, to detailed clinical-pathologic analysis in order to determine pathogenic relevance. By stratifying patients based on specific pathological features, we will increase the likelihood of identifying potential genetic contributions common to each category. Furthermore, there are pragmatic reasons for supporting additional research into MS pathology and genetics. A more fundamental understanding of the variable pathological and genetic factors involved in MS lesion evolution will not only provide additional pathogenetic insights into MS, but will lead to improved determination of long term prognoses, as well as impact the selection of current, and design of future, treatment approaches tailored to the patient.