Genomics of severe malaria complications in sickle cell disease

镰状细胞病严重疟疾并发症的基因组学

• 批准号: 9386347
• 负责人: Julie Makani
• 金额: $ 24.07万
• 依托单位: UNIVERSITY OF GHANA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9386347
• 关键词: Acute; Adult Respiratory Distress Syndrome; Affect; Africa; African; Anemia; Anti-Inflammatory Agents; Anti-inflammatory; Area; Birth; Brain; Brain Injuries; Cameroon; Cardiopulmonary; Case-Control Studies; Cell Adhesion Molecules; Cerebral Malaria; Cessation of life; Childhood; Chronic; Clinic; Clinical; Comorbidity; Country; Development; Diagnosis; Disease; Disease Progression; Enrollment; Evaluation; Gene Proteins; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Ghana; Heme; Hemoglobin; Hemolysis; Hospitalization; Immunologics; Infection; Inflammation; Inflammation Mediators; Inflammatory Response; Investigation; Life; Lung; Malaria; Malaria prevention; Measures; Methodology; Morbidity - disease rate; Mus; Neurological outcome; Nigeria; Organ; Parasites; Pathogenesis; Pathology; Patients; Phenotype; Physiological; Plasma; Plasmodium; Plasmodium berghei; Population; Predisposing Factor; Predisposition; Process; Proteins; Public Health; Recruitment Activity; Reperfusion Therapy; Research; Resources; Risk; Role; Severities; Severity of illness; Sickle Cell Anemia; Symptoms; Tanzania; Testing; Transgenic Organisms; Variant; base; chemokine; clinical phenotype; cohort; cytokine; cytotoxic; disease phenotype; disorder control; experience; genetic variant; genome-wide; improved; inflammatory marker; innovation; lung injury; malaria infection; mortality; mouse model; protein biomarkers; protein expression; sickling

PROJECT SUMMARY SickleGenAfrica is a genomics network that aims to test the overarching hypothesis that genetic variation in cyto-protective defenses against hemolysis influences the risk of organ damage in sickle cell disease (SCD). The focus of project 2 is to determine Genome-wide determinants of the risks of malaria complications in SCD. Background of the project: Malaria in SCD is associated with severe complications and an increased risk in mortality. Hemolysis is a key process that contributes to the pathogenetic processes in both malaria and SCD particularly with respect to acute and chronic end-organ damage leading to severe anemia, lung and brain injury. 4 countries in SickleGenAfrica (Ghana, Tanzania, Nigeria and Cameroon) and US collaborators (Pittsburgh and Morehouse) have experience and expertise in both conditions and intend to use established resources to interrogate the two conditions as well as establish a murine model to evaluate malaria in SCD. Specific aims: (1) To characterize the phenotype of severe malaria in SCD patients, and determine the relationship between variations in HCP genes and malaria disease phenotype/severity. (2) To investigate the inflammatory response (cytokines/chemokines and adhesion molecules) in SCD patients with malaria, and examine the relationship with HCP levels and risk of severe malaria. (3) Functionally validate association between HCPs and severity of malaria in transgenic SCD mice. The significance of the proposed research and relevance to public health: SCD and malaria are both disorder of public health significance (annual SCD births of 300,000 globally; 3.3 billion people living in 106 countries are at risk of malaria infection) with high mortality (Up to 90% childhood mortality in SCD; 438 000 malaria deaths). Accurate description of disease expression and the identification of genetic and environmental modifiers of disease will improve the diagnosis, management and prevention of malaria-related morbidity and mortality in SCD. The unique features and innovation of the project: (1) The first study with the largest SCD population (n=7,000) investigated for malaria. (2) Assessment of phenotypic description of malaria in SCD during acute and steady-state. (3) Evaluation of inflammatory response in malaria in SCD (4) Use of murine model to investigate malaria in SCD. The methodology to be used: We will enrol 7,000 SCD patients in 4 countries at clinic and evaluate patients during hospitalization. We will infect transgenic SCD and control mice with Plasmodium and measure levels of hemolysis cytoprotective proteins and inflammatory markers and evaluate disease expression focusing on hemolysis and anemia as well as end-organ damage to lung and brain. Expected results and description of how your results will affect other research areas: Description of phenotypic expression of co-morbidity of malaria and SCD, with identification of genetic and environmental modifiers of disease, emphasizing the role of hemolysis in both conditions.

项目摘要 镰刀法是一个基因组学网络，旨在检验遗传变异的总体假设 对溶血的细胞保护防御影响镰状细胞病（SCD）的器官损伤风险。 项目2的重点是确定全基因组的决定因素 scd。项目的背景：SCD中的疟疾与严重的并发症有关，并增加 死亡率的风险。溶血是一个关键过程，有助于疟疾和 SCD尤其是在急性和慢性末端器官损伤方面导致严重贫血，肺和 脑损伤。镰刀法（加纳，坦桑尼亚，尼日利亚和喀麦隆）和美国合作者的4个国家 （匹兹堡和莫尔豪斯）在这两种情况下都有经验和专业知识，并打算使用已建立的 询问这两种情况的资源以及建立鼠模型以评估SCD中的疟疾。 具体目的：（1）表征SCD患者中严重疟疾的表型，并确定 HCP基因的变异与疟疾疾病表型/严重程度之间的关系。 （2）调查 SCD疟疾患者的炎症反应（细胞因子/趋化因子和粘附分子）和 检查与HCP水平的关系和严重疟疾的风险。 （3）功能验证关联 在HCP和转基因SCD小鼠中疟疾的严重程度之间。拟议的研究的意义和 与公共卫生有关：SCD和疟疾都是公共卫生意义的障碍（年度SCD出生 全球30万；居住在106个国家的33亿人处于疟疾感染的风险） （SCD中最多90％的儿童死亡率； 438 000疟疾死亡）。疾病表达的准确描述 疾病的遗传和环境修饰符的鉴定将改善诊断， SCD中与疟疾相关的发病率和死亡率的管理和预防。独特的功能和 该项目的创新：（1）对疟疾进行了研究最大的SCD人群（n = 7,000）的第一项研究。 （2）评估急性和稳态期间SCD中疟疾的表型描述。 （3）评估 SCD中疟疾的炎症反应（4）使用鼠模型研究SCD中的疟疾。这 要使用的方法：我们将在诊所4个国家 /地区注册7,000名SCD患者，并评估患者 住院。我们将用疟原虫感染转基因SCD和对照小鼠的测量水平 溶血细胞保护蛋白和炎症标志物，并评估关注的疾病表达 溶血和贫血以及对肺和大脑的最终器官损害。预期结果和描述 您的结果将如何影响其他研究领域：合并症的表型表达的描述 疟疾和SCD，并鉴定出疾病的遗传和环境修饰符，强调了 在这两种情况下溶血。