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）：镰状细胞疾病（SCD）的挑战是一种点突变，它会在单个蛋白质中改变单个氨基酸，导致具有蛋白质表现的疾病。玛丽安·安德森（Marian Anderson）综合镰状细胞中心（MAC）在过去的研究中使用了生命的第一年，即生理上关键时期，以评估随着婴儿的增长而产生的生物生物标志物足迹。我们的研究最近表明，HBF不能保护HBS患者免受2年生命发生的内皮激活。但是，我们注意到这些生物标志物与溶血标记（例如LDH）相关。磷脂酰丝氨酸阳性（PS+）红细胞表现出渗透性脆弱性，在该循环群和内皮激活之间相关。 HBSS儿童的临床证据证实了我们的结果，因为年轻的HBSS患者的无声CNS梗塞率令人震惊。还注意到PS+红色细胞与异常的颅内TCD（Styles等人）相关，这还表明与大血管疾病的搭档相关。这样的研究使我们敏锐地意识到调节溶血仍然处于镰状细胞患者护理的最前沿。最近的临床试验令人沮丧，包括L-精氨酸，Gardos抑制剂，MG Pidaly受到副作用的困扰，血管成结clusion中的一氧化氮（NO）吸入仍在评估中。我们的两个项目（中心间试验和翻译）将评估溶血的新方法。首先，我们将使用NO（亚硝酸盐和BH4）的口服增强子来减少SCD中无关的内皮功能障碍，从而提供长期的血管舒张作用。转化项目将使用n-3脂肪酸补充剂来通过保护红细胞膜来减少溶血。鉴于Serhan等人的激动人心的工作，这项研究是新颖的，他最近表明eicosapentaenoic和docosahecahexaenoic酸是有效新化合物，保护素和分辨率的前体，可以阻止炎症时钟，并抑制缺血性缺血 - 再生 - 再生损伤。这项工作的另一个理由是，这些脂肪酸已被证明在HBSS疾病中血液循环细胞元素的膜上缺乏。我们已经与Serhan博士建立了合作，该博士将在我们的翻译项目中评估他的新颖调解人的水平。我们的基础科学项目通过将这一挑战解构为血红素和微粒的主要组成部分（分别给出并结合给伯克小鼠），从而利用了溶血的主题。我们将特别评估两个新区域，即proc凝位表型（基于我们在体外的演示，血红素会引起内皮TF表达）和粘合剂表型（我们的数据表明，血红素上调了内皮PS受体）。计划通过上游抑制剂调节溶血诱导的表型，还计划使用保护素和溶质蛋白。患者服务项目是一项创新的建议，旨在开发和评估针对SCD中QOL和学校功能的简短基于家庭的干预措施。如果成功，它的结果将可能会作为标准患者服务计划的一部分转移到镰状护理组织。对MAC大厦至关重要的是支持该中心不断增长的患者人群的专用人员的强大临床核心，其中包括费城和路易斯维尔的成人和儿童。将该中心围起来的是患者服务核心，通过宾夕法尼亚州和肯塔基州的教育和社区宣传，将我们的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