Pathogenesis of PCD Lung Disease

PCD 肺病的发病机制

• 批准号: 6729828
• 负责人: Michael R Knowles
• 金额: $ 36.67万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729828
• 关键词: biopsy; bronchial mucus; cell component structure /function; cilium; cilium /flagellum motility; clinical research; disease /disorder etiology; dynein ATPase; family genetics; genetic disorder; genetic markers; genetic polymorphism; human genetic material tag; human subject; linkage mapping; lung disorder; patient oriented research; phenotype; polymerase chain reaction; respiratory airflow disorder; respiratory airway clearance; respiratory epithelium; respiratory function; transmission electron microscopy; video microscopy

DESCRIPTION (provided by applicant): An important component of lung defense is the efficiency of mucociliary clearance (MCC). Primary ciliary dyskinesia (PCD) is a human genetic model of abnormal ciliary function and defective MCC. The overall goals of this project are to relate the molecular etiology of PCD to the ciliary phenotype (ultra structure; ciliary beat frequency and pattern). We hypothesize that certain abnormalities in ciliary ultra structure (particularly defective outer and inner dynein arms) reflect genetic mutations, and that discrete groups of genes encode each of those structures. Moreover, we hypothesize that mutations in genes encoding for outer dynein arm versus inner dynein arm proteins will be associated with different effects on ciliary beat frequency and waveform. Finally, we hypothesize that we will discover disease-causing mutations in PCD by a candidate gene approach, focused on genes encoding proteins in the dynein arms and central complex. To test our hypotheses, we have accumulated a cohort (n=86) of PCD patients who fulfill rigorous diagnostic criteria. In these (and an additional 60) PCD patients, we will determine ciliary ultra structure by transmission electron microscopy (TEM) and functional phenotype of PCD cilia using high-speed video-microscopy techniques. The strategy to test for disease-causing genetic mutations in PCD will use several different approaches, including an approach to narrow the search for candidate genes by using intra-genic polymorphisms, to test for "linkage" (exclusion mapping) within individual families. Taken together, these studies will allow us to determine correlations between ciliary ultra structure/function and genotype. Ultimately, we will develop a better understanding of the pathogenesis of airway disease resulting from abnormal ciliary function and defective mucociliary clearance. From a broader perspective, the identification of the genetic basis of PCD in patients with known ultrastructural defects will later provide the opportunity to test for "milder" genetic forms of ciliary dysfunction that predispose to more common airways diseases.

描述（由申请人提供）：肺防御的一个重要组成部分是粘膜清除（MCC）的效率。 原发性睫状运动障碍（PCD）是一种异常睫状功能和有缺陷MCC的人类遗传模型。 该项目的总体目标是将PCD的分子病因与睫状表型联系起来（超结构；睫状节拍频率和模式）。 我们假设睫状超结构（尤其是外部和内动力蛋白臂）中的某些异常反映了遗传突变，并且离散的基因组编码了这些结构中的每一个。 此外，我们假设编码外部动力蛋白手臂与内动力蛋白臂蛋白的基因突变将与对睫状节拍频率和波形的不同影响有关。 最后，我们假设我们将通过候选基因方法在PCD中发现引起疾病的突变，该方法的重点是编码动力蛋白臂和中央复合物中蛋白质的基因。 为了检验我们的假设，我们积累了符合严格诊断标准的PCD患者的队列（n = 86）。 在这些（和另外60）PCD患者中，我们将使用高速视频微观显微镜技术来确定透射电子显微镜（TEM）和PCD CILIA的功能表型。 在PCD中测试引起疾病的基因突变的策略将使用几种不同的方法，包括通过使用基因内多态性来缩小寻找候选基因的方法，以测试单个家庭中的“链接”（排除映射）。 综上所述，这些研究将使我们能够确定睫状超结构/功能和基因型之间的相关性。 最终，我们将更好地理解因睫状功能异常和缺陷的粘膜清除率而导致气道疾病的发病机理。 从更广泛的角度来看，在已知超微结构缺陷患者中对PCD的遗传基础的鉴定将在后来提供机会，以测试纤毛功能障碍的“温和”遗传形式，这些纤毛功能障碍易患更常见的气道疾病。