Genetic Determinants of Pathologic Heterogeneity in MS

描述（由申请人提供）：我们的初步研究表明，在炎症的病理测量、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病变存在个体内的同质性。个体间病理同质性的证据可能反映了控制病变形成的位点的遗传变异。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、再髓鞘和轴突损伤之间的复杂关系，并研究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，并更准确地确定每种病理表型内的病例数，以供未来的遗传研究。我们的目标是建立一个可靠和统计稳健的MS组织-DNA数据库，将病理学作为未来遗传关联研究的新中间结果。提议的研究将产生大量的患者材料资源，包括详细和定量的病理分析和DNA，并将为发现染色体区域或全基因组连锁感兴趣的候选基因提供高效和经济的过渡框架。人群关联和组织微阵列研究，以详细的临床病理分析，以确定致病的相关性。通过根据特定的病理特征对患者进行分层，我们将增加识别每个类别共同的潜在遗传贡献的可能性。此外，支持对多发性硬化症病理和遗传学进行进一步研究也有实际的原因。对多发性硬化症病变演变中涉及的可变病理和遗传因素的更基本的了解，不仅将为多发性硬化症提供额外的病理见解，而且将导致改善长期预后的确定，以及影响当前和未来针对患者量身定制的治疗方法的选择。

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.