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

描述（由申请人提供）：左心发育不全综合征（HLHS）是一种严重的、毁灭性的心脏缺陷，每年每5- 10000名新生儿中就有1名患有这种疾病，占先天性心脏病新生儿死亡总数的25%。HLHS的显著影响源于左侧心脏结构（二尖瓣、主动脉瓣和左心室）的损害。导致HLHS的病因机制尚不清楚，这使得预防方面的进展具有挑战性。遗传学研究表明，HLHS并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。我们对HLHS的发病机制提出了一种新的假说。我们的假设是，HLHS是一种形式的风湿性心脏病（RHD）在胎儿的表达。RHD是咽部溶血性a组链球菌感染的严重后遗症，最常表现为“链球菌性咽喉炎”。在RHD中，通过一种称为分子模仿的机制，在链球菌感染与人瓣膜和心肌抗原“交叉反应”时产生抗链球菌抗体。这会引发炎症和免疫级联，最终损害主动脉瓣/二尖瓣和邻近的左室。我们提出了HLHS发病机制的类似机制，其中母体抗体产生于对先前（和复发）链球菌感染的反应，穿过胎盘并损害易感宿主的胎儿心脏。胎儿瓣膜和左室的损伤导致血流改变，从而导致左室发育不全。缺乏HLHS的动物模型阻碍了可能转化为人类的研究。本提案的目的是建立HLHS的动物模型。在一种新的大鼠模型中，我们将证明经胎盘传递的抗体是对链球菌抗原免疫应答产生的，可导致后代具有hlhs样病理。在少数动物身上进行的初步研究证实了我们的建议的可行性。开发一种临床概括这种疾病的动物模型对于进一步提高对HLHS的理解、确定其发病机制以及潜在地确定治疗靶点至关重要。一个好的动物模型将对这一研究领域产生持续的影响。

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.