Molecular Biology of Marfan Syndrome

马凡氏综合症的分子生物学

• 批准号: 7931831
• 负责人: Harry C., III Dietz
• 金额: $ 28.31万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2011-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931831
• 关键词: Adrenergic Antagonists; Alleles; Angiotensin II; Animal Model; Animals; Aorta; Biological Assay; Cardiovascular system; Cell Culture System; Cells; Cessation of life; Clinical; Connective Tissue Diseases; Data; Defect; Development; Discrimination; Disease; Dose; Evaluation; Event; FBN1; Family; Fibroblasts; Foundations; Generations; Genes; Genetic; Growth Factor; Heterozygote; Histologic; Link; Losartan; Lung; MAPK14 gene; MAPK8 gene; Maps; Marfan Syndrome; Microsatellite Repeats; Missense Mutation; Modeling; Molecular; Molecular Biology; Mus; Mutation; Nature; Output; Pathway interactions; Patients; Performance; Phenotype; Phosphorylation; Proteins; Research Personnel; Rupture; Ruptured Aortic Aneurysms; SNP genotyping; Severities; Severity of illness; Signal Pathway; Signal Transduction; Skeletal Muscle; Smad Proteins; Smad protein; Stress; Syndrome; Therapeutic; Tissues; Transforming Growth Factor beta; Transgenic Organisms; Variant; Work; base; beta-adrenergic receptor; bone; clinically relevant; comparative efficacy; density; early childhood; epithelial to mesenchymal transition; genetic pedigree; genome wide association study; hemodynamics; homologous recombination; in vivo; inhibitor/antagonist; mouse model; mutant; neutralizing antibody; novel; overexpression; protective effect; receptor; research study; segregation; skeletal

Marfan syndrome (MFS) is a common connective tissue disorder, caused by fibrillin-1 mutations, that is associated with severe skeletal, ocular, and cardiovascular complications including death due to ruptured aortic aneurysms. Our prior work has shown that many manifestations of MFS are caused byexcessive activation of and signaling by TGFbeta, a family of growth factors that regulate cell performance and survival. Loeys-Dietz syndrome (LDS) is a newly recognized and apparently common disorder caused by mutations in either of the two genes that encode the TGFbeta receptor (TBR). MFS and LDS are intimately related conditions, both in terms of clinical manifestations and pathogenetic mechanisms. We believe that the integrated study of both disorders will be particularly powerful. Our foundations derived from prior study of mouse models of MFS will provide a meaningful context within which to interpret newly created animal models of LDS. This will include a dedicated assessment of the lung, bone, skeletal muscle, aorta, and valve leaflets in TBR-deficient animals, both with and without treatment with TGFbeta neutralizing antibody. In contrast to MFS (where signaling defects are initiated by matrix perturbations), the cell-autonomous nature of the defect in LDS will allow rapid and definitive evaluation of other potentially relevant pathogenetic events (including altered angiotensin II (Angll), p38, ERK1/2 and JNK signaling) using cell culture systems and pathway-specific pharmacologic antagonists; positive results will allow for hypothesis-driven interrogation of tissues derived from Marfan mice and patients. We will evaluate for genetic interactions in TBR mutant animals that are also deficient for fibrillin-1 or that conditionally overexpress Smad7, a natural inhibitor of TGFbeta. These data will help to segregate features of MFS that manifest either structural or regulatory (TGFbeta-related) deficiencies of fibrillin-1. Mouse studies will compare the efficacy of treatment with a beta- adrenergic receptor blocker (that lowers hemodynamic stress) with that for losartan (that both lowers hemodynamic stress and antagonizes TGFbeta) in the treatment of LDS, a devastating disorder associated with vessel rupture and death in early childhood. Results will inform our linkage effort to identify genetic modifiers of the MFS using exceptional pedigrees that show discrete variation in disease manifestations. Taken together, these data will facilitate the development of novel and rational therapeutic strategies.

Marfan综合征（MFS）是一种常见的结缔组织障碍，是由原纤维素-1突变引起的，即 与严重的骨骼，眼和心血管并发症有关，包括破裂而导致死亡 主动脉瘤。我们先前的工作表明，许多MF的表现都是由访问引起的 TGFBETA激活和信号传导，这是一个调节细胞性能和存活的生长因子家族。 Loeys-Dietz综合征（LDS）是由突变引起的新认识的，显然是常见的疾病 编码TGFBETA受体（TBR）的两个基因中的任何一个。 MFS和LD密切相关 条件，无论是临床表现和致病机制而言。我们相信 两种疾病的综合研究将特别有力。我们的基础是从事先研究 MF的鼠标模型将提供有意义的背景，以解释新创建的动物 LDS的模型。这将包括对肺，骨骼，骨骼肌，主动脉和瓣膜的专用评估 TBR缺陷动物中的小叶，无论是用TGFBETA中和抗体处理而没有治疗的小动物。在 与MF（通过基质扰动引发信号传导缺陷的情况），细胞自主性的性质 LDS中的缺陷将允许对其他潜在相关的致病事件进行快速和明确的评估 （包括细胞培养系统和 途径特定的药理学拮抗剂；积极的结果将允许假设驱动的审问 源自Marfan小鼠和患者的组织。我们将评估TBR突变体中的遗传相互作用 纤维蛋白-1或有条件过表达SMAD7的动物，一种天然抑制剂 TGFBETA。这些数据将有助于隔离表现结构或调节的MF的特征 （TGFBETA相关）原纤维素-1的缺陷。小鼠研究将比较治疗的疗效与β- 肾上腺素能受体阻滞剂（可以降低血液动力学胁迫）与氯沙坦（这两者都降低 血液动力学应力并拮抗TGFBETA）在LDS治疗中，与毁灭性疾病相关 童年时期的船只破裂和死亡。结果将为我们识别遗传的链接工作提供信息 MF的修饰符使用出色的血统，显示出疾病表现的离散变化。 综上所述，这些数据将促进新颖和理性的治疗策略的发展。