Investigation of the two-hit hypotesis for Cerebral Cavernous malformations

脑海绵状血管瘤二次打击假说的研究

• 批准号: 7544359
• 负责人: Amy Lee Akers
• 金额: $ 2.66万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-05-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7544359
• 关键词: Alleles; Anatomy; Appearance; Archives; Base Sequence; Biologically Based Therapy; Biology; Blood Vessels; Blood capillaries; Brain hemorrhage; CCM1 gene; Cancer Model; Categories; Cavernous Hemangioma; Cavernous Malformation; Cerebrum; Characteristics; Class; Classification Scheme; Cloning; Collection; Complex; Condition; Constitutional; Data; Development; Disease; Epilepsy; Event; Exhibits; Exons; Family history of; Future; Genes; Genetic; Germ-Line Mutation; Headache; Hearing; Hemangioma; Hemorrhage; Human; Incidence; Individual; Inheritance Patterns; Inherited; Investigation; Knowledge; Lesion; Malignant Neoplasms; Maps; Methodology; Modeling; Molecular; Molecular Genetics; Muscle Weakness; Mutate; Mutation; Mutation Analysis; Names; Nature; Neoplasms in Vascular Tissue; Neuraxis; Neurologic; Paralysed; Patients; Pattern; Proteins; RNA; Range; Recurrence; Retinoblastoma; Sampling; Scheme; Screening procedure; Site; Somatic Mutation; Staging; Stroke; Symptoms; Techniques; Testing; Time; Tissue Sample; Tissues; Tumor Suppressor Genes; Vascular remodeling; Vision; capillary; clinically relevant; design; lifetime risk; malformation; novel; novel strategies; tumor

DESCRIPTION (provided by applicant): Cerebral Cavernous Malformations (CCM) are vascular lesions of the central nervous system consisting of closely-packed, grossly-enlarged capillary-like vessels. CCM lesions develop through time from single dilated vessels into complex, multicavernous lesions and have a propensity for bleeding leading to hemorrhagic stroke. CCM may occur sporadically or follow an autosomal dominant pattern of inheritance. For the inherited condition, three loci have been mapped and the causative genes (CCM1, CCM2, and CCM3) have been identified. While the functions of these novel gene products have begun to be elucidated, there is no clear connection to their influence on lesion genesis or the mechanism for lesion progression. I hypothesize that CCM lesions arise due to a second-site somatic mutation leading to molecular homozygosity at the CCM gene locus. The two-hit hypothesis for CCM lesion genesis is consistent with the repeated observational difference between sporadic and familial CCM; multiple lesions develop in patients with familial CCM cases, but single lesions develop almost exclusively in sporadic cases. A similar pattern of incidence in familial and sporadic cases of retinoblastoma led to the development of a two-hit model by Knudson, in which both allelic copies of a tumor suppressor gene must be mutated to yield tumor formation. The two-hit hypothesis makes specific predictions for the mutational events leading to tumorogenesis in cancer. I propose to test these predictions for a non-cancer model; that of CCM using our collection of archived tissue samples. The two-hit hypothesis predicts that each class of CCM lesions, those with inherited mutations in CCM1, CCM2, or CCM3 will show somatic mutation within the lesion that is biallelic to the germline mutation. Additionally, the two-hit hypothesis predicts that sporadic CCM lesions will routinely harbor two distinct biallelic somatic mutations within one of the CCM genes. A key prediction of the two-hit hypothesis regarding the molecular genetic origins of multiple lesions in familial cases is that multiple lesions arise due to independent somatic mutational events. The following aims have been designed to comprehensively study the two-hit hypothesis using clinically-relevant mature human CCM lesion samples. 1a. To investigate the two-hit hypothesis in FAMILIAL cases of CCM. 1b. To validate the two-hit hypothesis in cases of familial CCM with MULTIPLE lesions 2. To investigate the two-hit hypothesis in SPORADIC cases of CCM. Through successful completion of these aims I intend to more fully understand the underlying fundamental biology of CCM, an inherited form of stroke, to impact future biologically-based therapy.

描述（由申请人提供）：脑海绵状血管瘤（CCM）是中枢神经系统的血管病变，由紧密堆积，严重扩张的毛细血管样血管组成。随着时间的推移，CCM病变从单一扩张的血管发展为复杂的多海绵状病变，并有出血倾向，导致出血性中风。CCM可能偶尔发生或遵循常染色体显性遗传模式。对于这种遗传性疾病，已经定位了三个基因座，并确定了致病基因（CCM1、CCM2和CCM3）。虽然这些新基因产物的功能已经开始被阐明，但它们对病变发生的影响或病变进展的机制还没有明确的联系。我假设CCM病变是由于第二位点体细胞突变导致CCM基因位点的分子纯合而引起的。CCM病变发生的双重打击假说与反复观察的散发性和家族性CCM之间的差异是一致的；家族性CCM病例中出现多个病变，但几乎只在散发病例中出现单个病变。在家族性和散发性视网膜母细胞瘤病例中，类似的发病率模式导致Knudson发展了双重打击模型，其中肿瘤抑制基因的两个等位基因拷贝必须突变才能产生肿瘤。双重打击假说对癌症中导致肿瘤发生的突变事件做出了具体的预测。我建议用一个非癌症模型来检验这些预测；CCM使用我们收集的存档组织样本。双重打击假说预测，每种类型的CCM病变，即具有CCM1、CCM2或CCM3遗传突变的CCM病变都会出现与种系突变双等位基因的体细胞突变。此外，双重打击假说预测，散发性CCM病变通常会在一个CCM基因中包含两个不同的双等位体细胞突变。关于家族性病例中多发病变的分子遗传起源的双重打击假说的一个关键预测是，多发病变是由独立的体细胞突变事件引起的。以下目标旨在使用临床相关的成熟人类CCM病变样本全面研究双重打击假设。