Complex Persistent Pain Conditions: Unique & Shared Pathways of Vulnerability

描述(由申请人提供)：目前的提案是对计划项目(2P01NS045685-06A1-PI Dr Maixner)的竞争性修订，在该项目中，我们建议探索线粒体遗传作为共病复杂持续性疼痛(CPP)条件的共同途径所起的作用。我们团队最近的数据表明，某些线粒体DNA(MtDNA)基因多态性与包括偏头痛和IBS在内的几种CPP有关，这表明能量代谢受损可能是一条共同的途径。在这次修订中，我们将探索整个线粒体DNA多态变化之间的关系，以确定与CPP相关的候选多态。这是CPP中要探索的一条新途径，并与计划项目的目标无缝契合。探索线粒体DNA，除了核DNA，心理和生理因素已经在该计划项目拨款，将加强我们对复杂的持续性疼痛障碍的共同风险因素的理解。为此，在项目拨款中获得的现有血液样本将用于基因分析，并辅之以储存的样本。在一组患者和对照组(N=400)中，我们将对整个mtDNA进行循环测序。在整个样本(N=1850)中，任何表现出与CPP潜在趋势关联的多态都将通过PCR-RFLP进行研究。此外，还将获得详细的家系，以确定功能性症状/障碍的母系遗传模式的存在和程度，以及与已识别的多态的关联。在线粒体DNA上收集的数据将与核遗传数据结合在一起，以便在PPG最初目标的范围内进行分析和建模。鉴定与疾病相关的mtDNA序列变异可以提供机制洞察和临床进展，并为理解cpp的mtDNA介导的多基因易感性建立新的致病模型。

DESCRIPTION (provided by applicant): The current proposal is a competitive revision to the Program Project (2P01NS045685-06A1-PI Dr Maixner) in which we propose to explore the role of mitochondrial inheritance as a shared pathway for co-morbid Complex Persistent Pain (CPP) conditions. Our group has recent data suggesting that certain mitochondrial DNA (mtDNA) polymorphisms are associated with several CPP, including migraine and IBS, suggesting that impaired energy metabolism may be a shared pathway. In this revision we will explore the relationship between polymorphic changes in the entire mtDNA to identify candidate polymorphisms associated with CPP. This is a novel pathway to be explored in CPP and fits seamlessly into the goals of the Program Project. Exploring mtDNA, in addition to nuclear DNA, psychological and physiological factors as already proposed in this program project grant, would enhance our understanding of the shared risk factors for complex persistent pain disorders. To this end, existing blood samples obtained in the project grant will be used for genetic analyses, supplemented with banked samples. In a subgroup (N=400) of patients and controls, we will cyclosequence the entire mtDNA. Any polymorphism demonstrating a potential trend association with CPP, will be studied by PCR-RFLP in the whole sample (N=1850). In addition, detailed pedigrees will be obtained to determine the presence and degree of a maternal inheritance pattern of functional symptoms/disorders and association with identified polymorphisms. Data collected on mtDNA will be integrated with nuclear genetic data for analysis and modeling within the original aims of the PPG. Identification of disease-associated mtDNA sequence variants could provide mechanistic insight and clinical advances, and establish a new pathogenic model for understanding mtDNA-mediated polygenic susceptibility in CPP.