Role of SP-A Gene Polymorphism in Lung Transplantation

SP-A基因多态性在肺移植中的作用

• 批准号: 8019013
• 负责人: Frank D'Ovidio
• 金额: $ 20.13万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8019013
• 关键词: Accounting; Address; Affect; Allografting; Bacteria; Biological Assay; Biological Markers; Biology; Biopsy; Bronchiolitis Obliterans; Calcineurin inhibitor; Cessation of life; Chronic; Clinical; Clinical Data; Code; Defense Mechanisms; Development; Dose; Environment; Environmental Risk Factor; Event; Exposure to; Failure; Functional disorder; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Glucocorticoids; Goals; Hamman-Rich syndrome; Heart Transplantation; Homeostasis; Host Defense Mechanism; Immune; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; In Vitro; Infection; Inflammation; Kidney Transplantation; Lung; Lung Lavage Fluid; Lung Transplantation; Lung diseases; Lymphocyte; Measures; Messenger RNA; Methods; Molecular; Natural Immunity; Opsonin; Organ; Organ Culture Techniques; Organ Transplant Research; Outcome; Pathologic; Patients; Performance; Pharmaceutical Preparations; Play; Postoperative Period; Proteins; Pulmonary Emphysema; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Proteins; Pulmonary Surfactants; Pulmonary function tests; RNA; Relative (related person); Research; Respiratory Failure; Restriction fragment length polymorphism; Role; Sampling; Selection Criteria; Serum; Solid; Staging; Steroids; Syndrome; Testing; Therapeutic; Tissue Sample; Transplant Recipients; Transplantation; Variant; Virus; activator 1 protein; allograft rejection; alveolar type II cell; antiproliferative agents; base; cohort; follow-up; fungus; genetic variant; graft failure; implantation; improved; in vitro Model; interest; liver transplantation; lung allograft; mRNA Expression; macrophage; mortality; novel; protein expression; public health relevance; respiratory distress syndrome; response; success; surfactant; tool

DESCRIPTION (provided by applicant): Lung transplantation is a widely accepted therapeutic option for end stage lung disease. However, clinical outcomes are yet challenged by primary graft failure, which is responsible for the majority of early mortality, and by chronic allograft dysfunction and chronic rejection, accounting for more than 30% of deaths after the third postoperative year. Lung transplantation offers a 50% recipient and graft 5-yr survival, which is significantly lower than for liver, kidney, and heart transplantation (over 70%). The ongoing lung's exposure to the environment is likely the determining factor, with a significant role being played by the performance of the defense mechanisms. Pulmonary surfactant proteins (SP) A, B, C, and D are one of the first host defense mechanisms the lung can mount. SP-A in particular, is an opsonin produced by the type II pneumocytes, and is active in the innate and adaptive immune system including regulating macrophage and lymphocyte responses. Of note, SP-A biologic activity seems to be genetically determined, and SP-A polymorphisms have been associated with various lung diseases including respiratory distress syndrome, idiopathic pulmonary fibrosis, and emphysema. We hypothesize that SP-A gene variability is responsible for the different tolerance of lung grafts to transplant-related noxious events. The two SP-A genes SP-A1 and SP-A2 have several polymorphisms within the coding region, SP-A1 (6A, 6A2- 20), and SP-A2 (1A, 1A0-13). In preliminary studies performed to test our hypothesis, donor lung SP-A1 and SP- A2 genetic variants were associated with survival and development of chronic lung dysfunction following transplantation. SP-A2 genotypes 1A0-1A2,3,5,9, were correlated with lower levels of SP-A mRNA within allografts at implantation and lower SP-A protein levels in the broncho-alveolar lavage fluid post transplantation. Moreover, patients who died within 30 days of transplantation had significantly lower levels of SP-A mRNA in their lung allografts at implantation. These preliminary findings obtained from a small cohort of patients suggest a new paradigm where genetically determined SP-A function contributes to allograft function and survival. We are proposing to evaluate, in an appropriately powered study, if SP-A gene polymorphisms predict primary graft dysfunction and/or chronic lung graft dysfunction, and if these polymorphisms could serve as biomarkers of lung graft dysfunction. We also propose to study the interaction between immunosuppressive drugs and SP- A expression and determine whether this is dependent on SP-A variants. In vitro studies have shown variable SP-A expression in response to steroids, one of the primary immunosuppressive drugs in lung transplantation. This proposal will generate novel information improving our understanding of lung allograft dysfunction. It is conceivable that the information obtained will stimulate the interest for a multi centre study to investigate if SP- A polymorphism may be integrated in the donor lung selection criteria and/or to implement post transplant tailored immunosuppression. PUBLIC HEALTH RELEVANCE: Lung transplantation related research has to date predominantly focused on recipient related immune biology, as done for other solid organ transplant research. This proposal will focus on donor innate immunity and will study surfactant protein A as a key molecule in the lung allograft organ specific, innate immunity. Surfactant protein A will be studied both at a genetic and protein level as a predictor and biomarker of lung allograft dysfunction. This study will increase our understanding of lung allograft dysfunction which is the major limiting factor for the long term success of lung transplantation.

描述（由申请人提供）：肺移植是一种广泛接受的终末期肺部疾病的治疗选择。然而，临床结果仍然受到原发性移植物失败的挑战，这是大多数早期死亡的原因，慢性同种异体移植物功能障碍和慢性排斥反应，占术后第三年后死亡人数的30%以上。肺移植提供了50%的受体和移植物5年存活率，这显著低于肝、肾和心脏移植（超过70%）。持续的肺暴露于环境可能是决定性因素，防御机制的性能发挥了重要作用。肺表面活性蛋白（SP）A、B、C和D是肺可以启动的第一宿主防御机制之一。特别是SP-A，是由II型肺细胞产生的调理素，并且在先天性和适应性免疫系统中具有活性，包括调节巨噬细胞和淋巴细胞应答。值得注意的是，SP-A生物活性似乎是由遗传决定的，SP-A多态性与各种肺部疾病相关，包括呼吸窘迫综合征、特发性肺纤维化和肺气肿。我们推测SP-A基因变异性是造成肺移植物对移植相关伤害事件耐受性不同的原因。两种SP-A基因SP-A1和SP-A2在编码区SP-A1（6A，6A 2 - 20）和SP-A2（1A，1A 0 -13）内具有几种多态性。在为检验我们的假设而进行的初步研究中，供体肺SP-A1和SP-A2遗传变异与移植后慢性肺功能障碍的存活和发展相关。SP-A2基因型1A 0 - 1A 2、3、5、9与移植时移植物内SP-A mRNA水平较低和移植后支气管肺泡灌洗液中SP-A蛋白水平较低相关。此外，在移植后30天内死亡的患者在植入时肺移植物中SP-A mRNA的水平显著较低。从一小群患者中获得的这些初步发现表明了一种新的范式，即遗传决定的SP-A功能有助于同种异体移植物的功能和存活。我们建议在一项具有适当把握度的研究中评估SP-A基因多态性是否可预测原发性移植肺功能障碍和/或慢性移植肺功能障碍，以及这些多态性是否可作为移植肺功能障碍的生物标志物。我们还建议研究免疫抑制药物和SP-A表达之间的相互作用，并确定这是否依赖于SP-A变体。体外研究表明，SP-A的表达对类固醇（肺移植中的主要免疫抑制药物之一）的反应是可变的。这一建议将产生新的信息，提高我们对肺移植功能障碍的理解。可以想象，所获得的信息将激发对多中心研究的兴趣，以研究SP-A多态性是否可以整合在供体肺选择标准中和/或实施移植后定制的免疫抑制。 公共卫生关系：与其他实体器官移植研究一样，肺移植相关研究迄今主要集中在受体相关免疫生物学上。该提案将集中于供体先天免疫，并将研究表面活性蛋白A作为肺移植器官特异性先天免疫的关键分子。将在遗传和蛋白质水平上研究表面活性蛋白A作为肺移植物功能障碍的预测因子和生物标志物。本研究将增加我们对肺移植功能障碍的认识，这是肺移植长期成功的主要限制因素。