Genetic Determinants of Pathologic Heterogeneity in MS

MS 病理异质性的遗传决定因素

• 批准号: 7418624
• 负责人: Claudia F. Lucchinetti
• 金额: $ 32.33万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7418624
• 关键词: Acute; Address; Affect; Antibodies; Apoptosis; Autopsy; B-Lymphocytes; Biopsy; Brain; Candidate Disease Gene; Categories; Chronic; Chronic Phase of Disease; Clinical; Complement; Complex; Control Locus; DNA; DNA Databases; Databases; Demyelinations; Development; Disease; Disease susceptibility; Distal; Evolution; Future; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Variation; Hereditary Disease; Heterogeneity; Hypoxia; Immune; Immunophenotyping; Individual; Inflammation; Inflammatory Response; Injury; Lead; Lesion; Measures; Mediating; Microglia; Multiple Sclerosis; Multiple Sclerosis Lesions; Numbers; Oligodendroglia; Outcome; Outcome Measure; Pathogenesis; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Plasma Cells; Population; Predisposition; Probability; Research; Resources; Risk Assessment; Sampling; Severities; Staging; Subgroup; T-Lymphocyte; Tissue Microarray; Tissues; Work; base; clinical phenotype; cost; density; design; genetic association; genome-wide linkage; improved; in vivo; injury and repair; insight; interest; macrophage; novel; outcome forecast; repaired

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.

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病变中存在个体内同质性。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。我们建议收集和病理表型的MS病变的大样本，以检查炎症，脱髓鞘，髓鞘再生和轴突损伤的早期和慢性MS病变之间的复杂关系，以及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学和免疫病理学结局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结果，并更准确地确定可用于未来遗传研究的每种相应病理表型中的病例数。我们的目标是建立一个可靠的和统计学上稳健的MS组织DNA数据库，该数据库将使用病理学作为未来遗传关联研究的新中间结果。拟议的研究将产生大量的患者材料资源，这些材料具有详细和定量的病理分析和DNA，并将提供一个有效和成本-从全基因组连锁、群体关联和组织微阵列研究中发现感兴趣的染色体区域或候选基因到详细的临床病理分析的有效过渡，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，我们将增加识别每个类别共同的潜在遗传贡献的可能性。此外，有务实的理由支持对MS病理学和遗传学的额外研究。对MS病变演变中涉及的可变病理和遗传因素的更基本的理解不仅将提供对MS的额外的发病机理见解，而且将导致改善长期疾病的确定，以及影响当前的选择和未来的设计，为患者量身定制的治疗方法。