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）：脑海绵状畸形（CCM）是中枢神经系统的血管病变，由密切包装的，严重的毛细血管样血管组成。 CCM病变从单个扩张的血管到复杂的多个病变，并具有出血倾向，导致出血性中风。 CCM可能偶尔发生或遵循常染色体主导遗传模式。对于遗传条件，已经映射了三个基因座，并确定了病因基因（CCM1，CCM2和CCM3）。尽管这些新型基因产物的功能已经开始阐明，但与它们对病变创世纪的影响或病变进展的机制尚无明确的联系。我假设CCM病变是由于第二个位点突变导致CCM基因基因座的分子纯合性而引起的。 CCM病变发生的两次打击假设与零星和家族性CCM之间反复的观察差异一致。家族性CCM病例患者发生多种病变，但单个病变几乎完全在零星病例中出现。在家族性和零星的视网膜细胞瘤病例中，类似的发生率模式导致了Knudson开发了两次打击模型，其中，必须将两个抑制肿瘤抑制基因的等位基因拷贝突变以产生肿瘤形成。两次打击的假设对导致癌症发生的突变事件做出了特定的预测。我建议为非癌症模型测试这些预测。 CCM使用我们收集的存档组织样品。两次打击的假设预测，每种CCM病变，CCM1，CCM2或CCM3中具有遗传突变的患者将在病变中显示出对种系突变的病变中的体细胞突变。此外，两次打击的假设预测，零星的CCM病变通常会在CCM基因之一内携带两个不同的双重体细胞突变。关于家族病变中多个病变的分子遗传起源的两次打击假设的关键预测是，由于独立的体细胞突变事件而引起多个病变。以下目标旨在全面研究使用临床上与成熟的人CCM病变样品的两次打击假设。 1a。研究CCM家族性病例中的两次打击假设。 1B。在具有多个病变的家族性CCM的情况下，验证两次打击的假设 2。研究CCM零星病例中的两次打击假设。 通过成功完成这些目标，我打算更充分了解CCM的基本生物学是一种遗传的中风形式，以影响未来的基于生物学的疗法。