Basic and Translational Research Program

描述（由申请人提供）：镰状细胞病的特征是剧痛发作和慢性器官损害，导致终末器官衰竭和过早死亡。尽管我们对病理生理学的理解有了显著的提高，但直接转化为帮助患者的治疗方法的进展相对较少。自引入羟基脲（一项重大治疗进展）以来的15年中，中位生存期并未改善，这一事实表明，获得专家护理是这些患者预后不良的另一个重要指标。这个项目的总体目标是探索可能产生新信息的研究途径，这些信息可以直接和快速地用于镰状细胞病患者的管理。为了实现这一目标，我们组建了一个由五家医疗机构、三个转诊小组和主要镰状细胞社区小组组成的联盟，他们多年来一直在一起工作，照顾南加州70%以上的镰状细胞患者。洛杉矶镰状细胞联盟（LASCC），包括加州镰状细胞疾病基金会将在五个对患者护理有直接影响的项目上进行合作：1)我们提出了一个中心间项目，以确定成人铁超载的患病率及其生理后果。2a)我们将检查慢性输血患者的非铁相关心功能障碍，并开展一项新的试点治疗试验，2b)我们将开展一项随机试点研究，以确定补充l -谷氨酰胺是否能改善运动耐量并减轻疼痛，3)我们将开展卫生服务研究，以确定为什么成人提供者不想照顾镰状病人，LASCC可以提供哪些服务来促进成人提供者的护理。我们设计的在服务点提供治疗援助的系统是否被利用和有效，以及突破性技术的使用是否可以改变试点社区急诊室或诊所的护理。我们还将确定项目2b中提出的治疗是否能改善生活质量和认知功能。5)我们将直接测量长期输血患者的大脑皮层氧输送、脑血流量和毛细血管血流量，并确定优化这些参数的HbS% /粘度。我们将进一步确定镰状细胞的替代标志物是否可以通过非侵入性的、临床适用的技术来测量，对HbS%的变化敏感，并与2b项目合作，通过补充l -谷氨酰胺来改善。该提案利用了洛杉矶团队的独特专业知识，并汇集了来自卫生服务研究、工程、生物物理学、心脏病学和营养科学等不同领域的研究人员的技能，以解决镰状细胞病管理和护理提供的关键方面。

DESCRIPTION (provided by applicant): Sickle cell disease is characterized by episodes of excruciating pain and chronic organ damage leading to end-organ failure and premature death. In spite of significant improvement in our understanding of the pathophysiology, relatively few advances have been directly translated into treatments that help patients. The fact that the median survival has not improved in the 15 years since the introduction of hydroxyurea, a major treatment advance, suggests that access to expert care is yet another significant poor prognostic indicator for these patients. The overall goal of this program project is to explore avenues of research that are likely to result in new information that can be directly and quickly used in the management of patients with sickle cell disease. To accomplish this, we have assembled a consortium of five medical institutions, three referral groups and the major sickle cell community group all of whom have been working together for many years to care for over 70% of the sickle cell patients in Southern California. The Los Angeles Sickle Cell Consortium (LASCC), including the Sickle Cell Disease Foundation of California will collaborate on five projects that have a direct impact on patient care: 1) we proposed an inter-center project to determine the prevalence of iron overload and its physiologic consequences in adults., 2a) we will examine non-iron related cardiac dysfunction in chronically transfused patients and carry out a novel pilot treatment trial, 2b) we will carry out a randomized pilot study to determine if supplementation with L-glutamine improves exercise tolerance and decreases pain, 3) we will carry out health services research to determine why adult providers don't want to care for sickle patients, what services could be provided by LASCC to facilitate care by adult providers, whether a system we have devised to provide treatment assistance at the point of service is utilized and effective, and whether use of breakthrough technologies can modify care at pilot community emergency rooms or clinics. We will also determine if the treatment proposed in project 2b results in improvement in quality of life and cognitive function, 5) we will directly measure cerebral cortex oxygen delivery, cerebral blood flow, and capillary blood flow in chronically transfused patients and determine the HbS% /viscosity that optimizes these parameters. We will further determine if surrogate markers of sickling that can be measured by non-invasive, clinically applicable techniques are sensitive to changes in HbS% and, in collaboration with project 2b, are improved by supplementation with L-glutamine. This proposal leverages the unique expertise of the Los Angeles team and brings together the skills of investigators from the diverse areas of health services research, engineering, biophysics, cardiology, and nutritional sciences to address critical aspects of sickle cell disease management and delivery of care.