Genome-wide map of Genetic Alteration in Human Pulmonary Hypertension Lungs

人类肺动脉高压肺遗传改变的全基因组图谱

• 批准号: 7898842
• 负责人: CHRISTOPHER D COLDREN
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898842
• 关键词: Affect; Aneuploidy; Architecture; Autologous; Cell Culture Techniques; Cell Proliferation; Cytogenetic Analysis; Cytogenetics; DNA; Development; Disease; Endothelial Cells; Endothelium; Etiology; Evaluation; Exhibits; Failure; Fluorescent in Situ Hybridization; Funding; Future; Gene Amplification; Gene Dosage; Gene-Modified; Genetic; Genome; Genomics; Genotype; Growth; Heart; Human; Hypertrophy; Individual; Inherited; Lead; Lesion; Loss of Heterozygosity; Lung; Lung diseases; Malignant Neoplasms; Maps; Microarray Analysis; Microsatellite Instability; Mutation; Oligonucleotides; Patients; Pattern; Play; Polymorphism Analysis; Pulmonary Hypertension; Pulmonary artery structure; Reagent; Receptor Gene; Recurrence; Research; Research Proposals; Role; Signal Transduction; Single Nucleotide Polymorphism; Structure of parenchyma of lung; Techniques; Technology; Tissue Sample; Tissues; Ursidae Family; Variant; Vasodilation; antiproliferative agents; arteriole; base; cancer therapy; comparative genomic hybridization; cost effective; genetic association; genetic linkage analysis; genome-wide; hypertension treatment; improved; insight; kindred; laser capture microdissection; monolayer; new technology; novel; pressure; programs; prospective; public health relevance; pulmonary arterial hypertension; treatment strategy; tumorigenesis

DESCRIPTION (provided by applicant): Pulmonary Arterial Hypertension (PAH) is a poorly understood, devastating disease. Lungs of patients with PAH exhibit dysregulated endothelial proliferation, in contrast to the monolayer endothelial cell architecture found in normal pulmonary arteries. This dysregulated endothelial proliferation manifests as neointima and plexiform lesions. Plexiform lesions from patients with Idiopathic Pulmonary Arterial Hypertension (IPAH) have been shown to be monoclonal and to exhibit microsatellite instability, two hallmarks of cancer. In research proposed here, we seek to characterize somatic genetic alterations in neointima and the plexiform lesion through a genome-wide search made possible by recent advances in microarray technology. This proposal will thereby extend the cancer paradigm of IPAH. The specific aims of this proposal are to characterize genetic alterations in proliferative endothelium from IPAH lungs using SNP arrays, and to verify and generalize these alterations using currently accepted standard cytogenetic techniques. The proposed genome-wide search is feasible because of recent developments in the technology and application of single nucleotide polymorphism (SNP) microarrays. We and others have demonstrated that genetic alterations such as loss of heterozygosity (LOH), gene amplification or deletion, aneuploidy, and uniparental isodisomy can be efficiently characterized across the entire genome using SNP arrays. Furthermore, these analyses can be conducted with the quantity and quality of genomic DNA that can be recovered from cell culture and from specially prepared fixed lung tissue sections subject to laser capture microdissection. Our research results will have a large impact on the conduct of future research into pulmonary hypertension. We anticipate that these exploratory studies will form the basis for an R01 funded research program investigating the functional consequences of the pathogenetics. Furthermore, I believe that novel treatment opportunities for IPAH will flow from the etiological understanding this research will produce. Treatment concepts have recently been expanded beyond vasodilatation to include a small number of antiproliferative agents. Our elucidation of IPAH etiology will allow us to leverage the "target-based" treatment paradigm employed in cancer therapy, and this targeted selection of antiproliferative agents for IPAH treatment will improve the likelihood that a lasting cure can be achieved. PUBLIC HEALTH RELEVANCE: Our discovery of recurrent patterns of genetic alteration in Idiopathic Pulmonary Arterial Hypertension lesions will direct us to disease modifying genes associated with the development of IPAH, and fundamentally change the understanding of IPAH pathobiology. Individuals suffering from PAH have limited treatment options, and by improving our understanding of this disease we hope to stimulate new and nascent treatment strategies.

描述（由申请人提供）：肺动脉高压（PAH）是一种知名度不佳，毁灭性的疾病。与正常肺动脉中发现的单层内皮细胞​​结构相反，PAH患者的肺部表现出失调的内皮增殖。这种失调的内皮增殖表现为新内膜和丛状病变。特发性肺动脉高压（IPAH）的患者的丛状病变已显示为单克隆人，表现出微卫星不稳定性，这是两个癌症的标志。在此处提出的研究中，我们试图通过微阵列技术的最新进步来表征新内膜菌和丛生病变的体细胞遗传改变和丛生的病变。因此，该提议将扩大IPAH的癌症范式。该提案的具体目的是表征使用SNP阵列从IPAH肺部增生性内皮中的遗传改变，并使用当前接受的标准细胞遗传学技术验证和概括这些改变。拟议的全基因组搜索是可行的，这是因为单核苷酸多态性（SNP）微阵列的最新发展和应用。我们和其他人已经证明，遗传改变，例如杂合性丧失（LOH），基因扩增或缺失，非整倍性和单亲异构造期，可以在整个基因组中有效地表征SNP阵列。此外，这些分析可以用基因组DNA的数量和质量进行，这些基因组DNA可以从细胞培养物中回收，并从经受激光捕获微分解的特殊准备的固定肺组织切片中进行。我们的研究结果将对未来对肺动脉高压的研究的行为产生重大影响。我们预计这些探索性研究将构成R01资助的研究计划的基础，研究病原体的功能后果。此外，我认为，IPAH的新型治疗机会将从这项研究产生的病因理解中流动。最近，已经扩展了治疗概念，超出了血管舒张，包括少量抗增殖剂。我们阐明IPAH病因将使我们能够利用癌症治疗中采用的“基于目标”的治疗范例，而目标选择抗增殖剂进行IPAH治疗将改善可以实现持久治疗的可能性。 公共卫生相关性：我们发现特发性肺动脉高压损伤中遗传改变的经常性模式将指导我们疾病改变与IPAH发展相关的基因，并从根本上改变对IPAH病理生物学的理解。患有PAH的人的治疗选择有限，并且通过提高我们对这种疾病的理解，我们希望刺激新的和新生的治疗策略。