Basic and Translational Research Program (BTRP) in Sickle Cell Disease

镰状细胞病基础与转化研究计划 (BTRP)

• 批准号: 7813845
• 负责人: MARIE J. STUART
• 金额: $ 13.25万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7813845
• 关键词: Basic; Translational; Research; Program; BTRP

DESCRIPTION (provided by applicant): The challenge of sickle cell disease (SCD) is how a point mutation, which changes a single amino acid in a single protein, causes a disease with protean manifestations. The Marian Anderson Comprehensive Sickle Cell Center (MAC) has in past studies used the first years of life, a physiologically crucial period, to evaluate the biologic biomarker footprint created as the infant grows. Our studies have recently demonstrated that HbF does not protect patients with HbSS against endothelial activation which occurs by 2 years of life. We note, however, that these biomarkers correlate with markers of hemolysis such as LDH. Phosphatidylserine-positive (PS+) erythrocytes demonstrate osmotic fragility, with correlates between this circulating cohort and endothelial activation. Clinical evidence in the child with HbSS confirms our results, since there is an alarming rate of silent CNS infarction in the young HbSS patient. PS+ red cells were also noted to correlate with abnormal intracranial TCDs (Styles et al), suggesting additionally a tie-in with large vessel disease. Such studies make us acutely aware that modulating hemolysis remains at the forefront of sickle cell patient care. Recent clinical trials have been disheartening including L-Arginine, a Gardos Inhibitor, Mg Pidolate is beset with side effects, and nitric oxide (NO) inhalation in vasocclusion is still under evaluation. Two of our projects (Inter-Center Trial and Translational) will evaluate novel approaches to hemolysis. In the first, we will use oral enhancers of NO (nitrite and BH4) to decrease NO-related endothelial dysfunction in SCD by providing a long term vasodilatory effect. The translational project will use n-3 fatty acid supplementation to reduce hemolysis by protecting the red cell membrane. This study is novel in light of exciting work by Serhan et al, who recently showed that Eicosapentaenoic and Docosahexaenoic acids are precursors of potent new classes of compounds, the Protectins and Resolvins that stop the clock on inflammation, and inhibit ischemia-reperfusion injury. An additional rationale for this work is that these fatty acids have been shown to be deficient in the membranes of the circulating cellular elements of blood in HbSS disease. We have forged a collaboration with Dr. Serhan who will assess levels of his novel mediators in our Translational Project. Our Basic Science Project capitalizes on the theme of hemolysis by deconstructing this challenge into its major components of heme and microparticles (given separately and in combination to Berk mice). We will specifically assess two new areas, i.e. procoagulant phenotype (based on our demonstration in vitro that heme causes endothelial TF expression), and an adhesive phenotype (our data demonstrates that heme upregulates an endothelial PS receptor). Modulation of hemolysis-induced phenotypes by upstream inhibitors is planned, and also the use of Protectins and Resolvins. The Patient Services Project is an innovative proposal to develop and evaluate a brief family-based intervention targeting QoL and school functioning in SCD. If successful, its results will be potentially transferable to sickle care organizations as part of standard patient services programs. Crucial to the MAC edifice is a robust clinical core of dedicated staff supporting the Center's growing patient population, which includes adults and children in Philadelphia and Louisville. Rounding out the Center is a patient services core translating our state of the art research and patient care into practice through education and community outreach in Pennsylvania and Kentucky.

描述（由申请人提供）：镰状细胞病（SCD）的挑战是改变单个蛋白质中的单个氨基酸的点突变如何导致具有多变表现的疾病。玛丽安·安德森综合镰状细胞中心 (MAC) 在过去的研究中利用生命的最初几年（生理上的关键时期）来评估婴儿成长过程中产生的生物标志物足迹。我们最近的研究表明，HbF 不能保护 HbSS 患者免受 2 岁时发生的内皮激活的影响。然而，我们注意到这些生物标志物与溶血标志物（如 LDH）相关。磷脂酰丝氨酸阳性（PS+）红细胞表现出渗透脆性，该循环群体与内皮激活之间存在相关性。 HbSS 儿童的临床证据证实了我们的结果，因为年轻 HbSS 患者中无症状中枢神经系统梗塞的发生率惊人。 PS+ 红细胞还被发现与颅内 TCD 异常相关（Styles 等人），这表明另外与大血管疾病有关。这些研究使我们敏锐地意识到调节溶血仍然是镰状细胞病患者护理的最前沿。最近的临床试验令人沮丧，包括L-精氨酸（一种 Gardos 抑制剂）、吡酮酸镁的副作用以及吸入一氧化氮 (NO) 治疗血管闭塞的效果仍在评估中。我们的两个项目（中心间试验和转化）将评估溶血的新方法。首先，我们将使用 NO 口服增强剂（亚硝酸盐和 BH4）通过提供长期血管舒张作用来减少 SCD 中与 NO 相关的内皮功能障碍。该转化项目将使用 n-3 脂肪酸补充剂，通过保护红细胞膜来减少溶血。鉴于 Serhan 等人令人兴奋的工作，这项研究是新颖的，他们最近表明二十碳五烯酸和二十二碳六烯酸是有效的新型化合物的前体，即保护素和分解素，它们可以停止炎症时钟并抑制缺血再灌注损伤。这项工作的另一个理由是，在 HbSS 疾病中，这些脂肪酸已被证明在血液循环细胞成分的膜中缺乏。我们已经与 Serhan 博士建立了合作，他将在我们的转化项目中评估他的新颖调解者的水平。我们的基础科学项目利用溶血这一主题，将这一挑战解构为血红素和微粒的主要成分（分别给予伯克小鼠和联合给予）。我们将具体评估两个新领域，即促凝血表型（基于我们在体外证明血红素引起内皮 TF 表达）和粘附表型（我们的数据表明血红素上调内皮 PS 受体）。计划通过上游抑制剂调节溶血诱导的表型，并使用 Protectins 和 Resolvins。患者服务项目是一项创新提案，旨在制定和评估针对 SCD 的生活质量和学校功能的简短家庭干预措施。如果成功，其结果将有可能作为标准患者服务计划的一部分转移到镰刀护理组织。 MAC 大厦的关键是拥有一支由敬业的工作人员组成的强大的临床核心，为该中心不断增长的患者群体提供支持，其中包括费城和路易斯维尔的成人和儿童。该中心的另一个核心是患者服务核心，通过宾夕法尼亚州和肯塔基州的教育和社区外展，将我们最先进的研究和患者护理转化为实践。

项目成果

Introduction to special section: advancing research on the intersection of families, culture, and health outcomes.

专题介绍：推进家庭、文化和健康结果交叉点的研究。

• DOI: 10.1093/jpepsy/jss081
• 发表时间: 2012
• 期刊: Journal of pediatric psychology
• 影响因子: 3.6
• 作者: McQuaid,ElizabethL;Barakat,LamiaP
• 通讯作者: Barakat,LamiaP

Family Functioning, Medical Self-Management, and Health Outcomes Among School-Aged Children With Sickle Cell Disease: A Mediation Model.

镰状细胞病学龄儿童的家庭功能、医疗自我管理和健康结果：中介模型。

• DOI: 10.1093/jpepsy/jsx120
• 发表时间: 2018
• 期刊: Journal of pediatric psychology
• 影响因子: 3.6
• 作者: Psihogios,AlexandraM;Daniel,LaurenC;Tarazi,Reem;Smith-Whitley,Kim;Patterson,ChavisA;Barakat,LamiaP
• 通讯作者: Barakat,LamiaP

Increased von Willebrand factor antigen and high molecular weight multimers in sickle cell disease associated with nocturnal hypoxemia.

与夜间低氧血症相关的镰状细胞病中冯维勒布兰德因子抗原和高分子量多聚体增加。

• DOI: 10.1016/j.thromres.2007.12.004
• 发表时间: 2008
• 期刊: Thrombosis research
• 影响因子: 7.5
• 作者: Krishnan,Suba;Siegel,Jamie;PullenJr,Gene;Hevelow,Megan;Dampier,Carlton;Stuart,Marie
• 通讯作者: Stuart,Marie