Developing an animal model of HLHS: role of immune mediated injury

描述（由申请人提供）：左心发育不良综合征（HLHS）是一种严重和毁灭性的心脏缺陷，每年影响约1/5- 10，000的新生儿，占先天性心脏病所有新生儿死亡的25%。HLHS的显著影响源于左侧心脏结构（二尖瓣和主动脉瓣以及左心室或LV）受损。导致HLHS的病因机制尚不清楚，这使得预防进展具有挑战性。遗传学研究表明，HLHS不遵循简单的孟德尔遗传学，而是表现出遗传和环境因素共同作用的“复杂遗传”。我们的长期目标是通过更好地了解其发病机制来帮助根除HLHS。 我们提出了一个新的假说HLHS的发病机制。我们的假设是HLHS是胎儿风湿性心脏病（RHD）的一种表现形式。风湿性心脏病是一种严重的后遗症咽部ss-溶血性A组链球菌（链球菌）感染，最常见的表现形式为“链球菌咽喉”。在风湿性心脏病中，抗链球菌抗体是通过一种称为分子模拟的机制与人瓣膜和心肌抗原发生交叉反应而产生的。这引发了炎症和免疫级联反应，最终损害主动脉瓣/二尖瓣和相邻LV。我们提出了一个类似的机制HLHS的发病机制，其中母体抗体产生的前期（和复发）链球菌感染，穿过胎盘和损伤胎儿心脏的易感主机。胎儿瓣膜和左心室的损伤导致血流改变，进而导致左心室发育不全。 缺乏HLHS的动物模型阻碍了可能转化为人类的研究。本研究的目的是建立一种HLHS动物模型。在一个新的大鼠模型中，我们将表明，经胎盘传递的抗体产生的反应与链球菌抗原的免疫接种，可导致后代与HLHS样病理。在少数动物身上进行的初步研究证实了我们建议的可行性。 开发一种在临床上重现这种疾病的动物模型对于进一步努力提高对HLHS的理解和定义其发病机制以及潜在地识别治疗靶点是至关重要的。一个好的HLHS动物模型将对这一研究领域产生持续的影响。 公共卫生相关性：心脏缺陷是出生缺陷的头号原因。左心发育不良综合征（HLHS）占所有因心脏病死亡的新生儿的25%。目前尚无法开发HLHS动物模型的拟议研究将显著影响HLHS病因的研究和这种毁灭性疾病的管理。

DESCRIPTION (provided by applicant): Hypoplastic left heart syndrome (HLHS) is a severe and devastating heart defect that affects ~ 1 in 5-10,000 children born each year and accounts for 25% of all neonatal deaths from congenital heart disease. The significant impact of HLHS stems from a compromise of left- sided cardiac structures (mitral and aortic valves and the left ventricle or LV). Etiologic mechanisms leading to HLHS are unknown making advances in prevention challenging. Genetic studies show that HLHS does not follow simple Mendelian genetics but exhibits "complex inheritance" with contributions from both genetic and environmental factors. Our long- term goal is to help eradicate HLHS through better understanding of the mechanism(s) involved in its pathogenesis. We propose a novel hypothesis for the pathogenesis of HLHS. Our hypothesis is that HLHS is an expression of a form of rheumatic heart disease (RHD) in the fetus. RHD is a serious sequelae of pharyngeal ss-hemolytic group A streptococcal (strep) infection, most commonly manifest in the form of "strep throat". In RHD anti-strep antibodies are generated in response to the strep infection "cross-react" with human valvular and myocardial antigens, through a mechanism known as molecular mimicry. This initiates an inflammatory and immunologic cascade that ultimately damages the aortic/mitral valves and the adjacent LV. We propose a similar mechanism for the pathogenesis of HLHS in which maternal antibodies produced in response to antecedent (and recurrent) strep infection, cross the placenta and damage the fetal heart in the susceptible host. The injury to the fetal valves and LV causes alterations in flow that then leads to LV hypoplasia. Lack of animal models of HLHS has hindered research that could translate to humans. The goal of this proposal is to develop a animal model of HLHS. In a novel rat model we will show that transplacental passage of antibodies produced in response to prior immunization with strep antigens can lead to offspring with HLHS-like pathology. Preliminary studies in a small number of animals have confirmed the feasibility of our proposal. Development of an animal model that clinically recapitulates this disease is essential to furthering the efforts to improve understanding of HLHS and define its mechanisms of pathogenesis as well as potentially identify therapeutic targets. A good animal model for HLHS will have a sustained impact on this field of research. PUBLIC HEALTH RELEVANCE: Heart defects are the #1 cause of birth defects. Hypoplastic Left Heart Syndrome or HLHS accounts for 25% of all neonatal deaths from heart disease. The proposed studies to develop an animal model of HLHS, currently unavailable, will significantly impact research into causes of HLHS and management of this devastating disease.