Sickle Cell Anemia, Splenic Pathology, and Hydroxyurea in Sub-Saharan Africa

撒哈拉以南非洲地区的镰状细胞性贫血、脾脏病理学和羟基脲

基本信息

批准号：
10040082
负责人：
Luke Smart
金额：
$ 16.96万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-21 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10040082
关键词：
18 year old 3-Dimensional 5 year old Address Adult Affect Africa Africa South of the Sahara African Age Age-Months Anatomy Atrophic Attention Biometry Cell Adhesion Child Clinical Clinical Research Clinical Trials Clinical Trials Design Country Data Data Analyses Development Plans Diagnosis Disease Dose Enrollment Environment Erythrocytes Etiology Event Fetal Hemoglobin Filtration Frequencies Functional disorder Future Goals Guidelines Hematological Disease Immune response Immunology Incidence Infection Inflammation Inherited Knowledge Laboratories Life Malaria Maximum Tolerated Dose Measurement Medical center Mentored Patient-Oriented Research Career Development Award Mentors Mentorship Morbidity - disease rate National Heart, Lung, and Blood Institute Neonatal Screening Ohio Organ Outcome Palpable Participant Pathology Patients Pediatric Hospitals Penicillins Persons Physiology Predisposition Prevalence Prevention program Prophylactic treatment Publishing Research Research Personnel Resources Risk Risk Factors Safety Serologic tests Sickle Cell Sickle Cell Anemia Spleen Splenomegaly Statistical Methods Stroke Stroke prevention Tanzania Testing Time Toxic effect Training Transfusion Translational Research Ultrasonography United States Food and Drug Administration Vaccination Vaccines Viral Work alpha thalassemia minor alpha-Thalassemia base blood rheology career development clinical effect clinical infrastructure cohort collaborative environment effective therapy evidence base experience functional status hydroxyurea immune function improved improved outcome laboratory experience malaria infection mortality peripheral blood preservation programs prospective response safety and feasibility screening program treatment comparison treatment group treatment trial

项目摘要

PROJECT SUMMARY/ABSTRACT Research: Contrary to children in the US with sickle cell anemia (SCA) who develop dysfunctional, atrophic spleens by 5 years old, children with SCA in sub-Saharan Africa often have splenomegaly, but its functional status and clinical consequences are unknown. The long-term goal of this research is to understand the etiology, pathophysiology, and clinical consequences of splenomegaly in children with SCA in sub-Saharan Africa. The goal of this proposal is to investigate the etiology and clinical effects of splenomegaly both before and after hydroxyurea treatment in a large cohort of children with SCA, enrolled in a prospective treatment trial (SPHERE, NCT03948867). The candidate's ancillary trial will collect serial measurements of both splenic volume (3-dimensional ultrasound) and splenic function (Howell Jolly bodies, pitted red blood cells, and specific viral serologies) in both the observation and the treatment groups of the SPHERE cohort and address these specific aims: 1) identify factors associated with splenomegaly prior to treatment and correlate anatomy (3-dimensional volume) with physiology (filtrative and immunological functions) and 2) investigate changes in splenic volume and function during hydroxyurea treatment as well as laboratory and clinical effects of hydroxyurea compared to untreated participants. These aims will test the following hypotheses: 1A) baseline splenomegaly will be present in 10-20% and associated with alpha thalassemia and previous malaria infections; 1B) pre-treatment splenic size will not correlate with function; 2A) incidence of splenomegaly will double in children receiving hydroxyurea compared to untreated children and be predicted by pre-treatment splenic volume, HbF response, and new malarial infections; 2B) splenomegaly with hydroxyurea treatment will be associated with improved splenic filtrative function and preserved immunological function. Career Development Plan: Dr. Smart's long-term goal is to become an independent investigator focused on improving outcomes for persons with sickle cell disease in the US and globally. He will pursue the following objectives during his K23 training: 1) obtain mentorship in the implementation of rigorous clinical trials in low- resource settings by conducting a prospective clinical trial among children with SCA in Tanzania; 2) understand the significance of splenic dysfunction in SCA through educational seminars and laboratory experience that includes quantitative and qualitative assessments of spleen anatomy and physiology; and 3) gain experience in clinical trial design and advanced statistical methods through coursework and data analysis. Environment: The proposed research will be conducted at Cincinnati Children's Hospital Medical Center (Cincinnati, Ohio) and Bugando Medical Centre (Mwanza, Tanzania) who have a longstanding partnership that provides a strong collaborative environment with infrastructure for clinical and translational research, outstanding mentorship, and an excellent team of collaborators with expertise in sickle cell disease, immunology, hydroxyurea therapy, biostatistics, and clinical trials in low-resource settings.

项目概要/摘要研究：与美国患有镰状细胞性贫血 (SCA) 的儿童相反，他们会出现功能障碍、萎缩撒哈拉以南非洲的 SCA 儿童在 5 岁时脾脏通常出现肿大，但其功能正常状态和临床后果尚不清楚。这项研究的长期目标是了解撒哈拉以南地区 SCA 儿童脾肿大的病因、病理生理学和临床后果非洲。该提案的目的是在之前调查脾肿大的病因和临床效果对一大群患有 SCA 的儿童进行羟基脲治疗后，参加了一项前瞻性治疗试验（球体，NCT03948867）。候选人的辅助试验将收集两个脾脏的连续测量结果体积（3 维超声）和脾功能（Howell Jolly 小体、凹陷红细胞和 SPHERE 队列的观察组和治疗组中的特定病毒血清学）并解决这些具体目标：1) 在治疗前确定与脾肿大相关的因素并关联解剖学（3 维体积）与生理学（过滤和免疫功能）和 2）研究变化羟基脲治疗期间的脾体积和功能以及实验室和临床效果羟基脲与未治疗的参与者相比。这些目标将检验以下假设：1A) 10-20% 的人会出现基线脾肿大，并与 α 地中海贫血和既往疟疾有关感染； 1B) 治疗前脾脏大小与功能无关； 2A) 脾肿大的发生率接受羟基脲的儿童是未治疗儿童的两倍，并且可以通过治疗前预测脾脏体积、HbF 反应和新发疟疾感染； 2B) 羟基脲治疗会导致脾肿大与改善脾脏滤过功能和保留免疫功能有关。职业发展计划：Smart博士的长期目标是成为一名专注于以下领域的独立研究者改善美国和全球镰状细胞病患者的治疗结果。他将追求以下目标 K23 培训期间的目标：1）获得在低水平环境中实施严格临床试验的指导通过在坦桑尼亚的 SCA 儿童中进行前瞻性临床试验来设置资源； 2）通过教育研讨会和实验室了解 SCA 中脾功能障碍的重要性包括对脾脏解剖学和生理学进行定量和定性评估的经验；和 3) 通过课程作业和数据分析获得临床试验设计和先进统计方法的经验。环境：拟议的研究将在辛辛那提儿童医院医疗中心进行（俄亥俄州辛辛那提）和布甘多医疗中心（坦桑尼亚姆万扎）有着长期的合作伙伴关系为临床和转化研究提供强大的协作环境和基础设施，出色的指导和具有镰状细胞病专业知识的优秀合作者团队，免疫学、羟基脲治疗、生物统计学和资源匮乏环境中的临床试验。