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

建立 HLHS 动物模型：免疫介导损伤的作用

• 批准号: 8190837
• 负责人: Pirooz Eghtesady
• 金额: $ 22.69万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-25 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190837
• 关键词: Accounting; Affect; Age; Animal Model; Animals; Antibodies; Antigens; Binding; Biological Assay; Blood flow; Cardiac; Cardiac Myosins; Carditis; Cesarean section; Child; Clinical Research; Complex; Congenital Abnormality; Congenital Heart Defects; Control Animal; Data; Developmental Delay Disorders; Disease; Echocardiography; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Exhibits; Female; Fetal Heart; Fetus; Funding; Future; Genetic; Goals; Heart; Heart Block; Heart Diseases; Histology; Human; Hypoplastic Left Heart Syndrome; Immune; Immunization; Immunoglobulin Deposition; Immunoglobulin G; Immunoglobulins; Immunohistochemistry; Immunologics; Infection; Inflammatory; Injury; Interferon Type II; Interleukins; Lead; Left; Left ventricular structure; Lesion; Maternal antibody; Measures; Mediating; Medical; Mitral Valve; Modeling; Molecular; Molecular Mimicry; Morbidity - disease rate; Mothers; Myocardial; Myocardial tissue; Operative Surgical Procedures; Outcome; Partner in relationship; Pathogenesis; Pathology; Pharyngeal structure; Placenta; Pregnancy; Preparation; Prevention; Process; Protocols documentation; Quality of life; Rattus; Recurrence; Reporting; Research; Rheumatic Heart Disease; Role; Saline; Serum; Severities; Side; Streptococcal Infections; Structure; Support System; Testing; Tissues; Translating; Tumor Necrosis Factor-alpha; United States National Institutes of Health; animal model development; aortic valve; base; clinically relevant; congenital heart disorder; fetal; improved; inflammatory marker; maternal serum; mortality; neonatal death; novel; offspring; palliation; prevent; response; stem; therapeutic target

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.

描述(申请人提供)：左心发育不全综合征(HLHS)是一种严重的破坏性心脏缺陷，每年影响到每5-10,000名新生儿中就有1人受到影响，占所有先天性心脏病新生儿死亡的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)的折衷。导致HLHS的病因机制尚不清楚，这给预防方面的进展带来了挑战。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HLHS的发病机制(S)来帮助根除HLHS。我们对HLHS的发病机制提出了一个新的假说。我们的假设是HLHS是风湿性心脏病(RHD)在胎儿中的一种表现形式。风湿性心脏病是A组咽部溶血性链球菌(STEP)感染的严重后遗症，最常见的表现为“链球菌咽喉”。在风湿性心脏病中，抗链球菌抗体是对链球菌感染的反应而产生的，通过一种被称为分子拟态的机制与人类瓣膜和心肌抗原发生交叉反应。这会引发炎症和免疫级联反应，最终损害主动脉瓣/二尖瓣和邻近的左室。我们对HLHS的发病机制提出了类似的机制，即母体抗体对先前(和反复)的链球菌感染做出反应，穿过胎盘，损害易感宿主的胎儿心脏。胎儿瓣膜和左心室的损伤会导致血流改变，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。这项建议的目的是开发一种HLHS的动物模型。在一个新的大鼠模型中，我们将证明通过胎盘途径产生的抗体可以导致子代出现类似HLHS的病理。对少数动物的初步研究证实了我们的建议的可行性。开发一种临床上概括这种疾病的动物模型对于进一步努力提高对HLHS的理解、确定其发病机制以及潜在的治疗靶点至关重要。一个好的HLHS动物模型将对这一研究领域产生持续的影响。 与公共健康相关：心脏缺陷是导致出生缺陷的头号原因。左心发育不全综合征或HLHS占所有新生儿心脏病死亡的25%。发展HLHS动物模型的拟议研究目前还无法获得，这将对HLHS的病因研究和这种毁灭性疾病的管理产生重大影响。