Biomakers in Sickle Cell Anemia: Response to Hydroxyurea

镰状细胞性贫血的生物制造者：对羟基脲的反应

• 批准号: 6785922
• 负责人: MARIE J. STUART
• 金额: $ 38万
• 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: 2003-08-04 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6785922
• 关键词: biomarker; cell cell interaction; clinical research; erythrocytes; hemoglobin F; human subject; human therapy evaluation; hydroxyurea; patient oriented research; pediatric pharmacology; placebos; preschool child (1-5); sickle cell anemia

DESCRIPTION (provided by applicant): In a landmark clinical trial, oral hydroxyurea (HU) decreased the frequency of vaso-occlusive crises and acute chest syndrome, and reduced the need for transfusions and hospitalizations in adult patients with homozygous SS disease (HbSS). While the consensus from this study, and others is that HU has pleotropic modes of action in HbSS with effects on HbF, dense cells, reticulocytes, white cells and red cell-endothelial interactions, the relative merits of these individual modes of action on disease amelioration are not known. The NHLBI will be conducting a pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) in which HU will be tested in a randomized double-blinded, placebo-controlled trial for the prevention of chronic organ damage in 200 infants with HbSS. As a prelude to the major study, in 2003, a pilot Baby HUG randomized placebo-controlled, two-year trial of 40 infants (ages 12 to 17 months at study entry) will be conducted to ascertain the feasibility of the larger proposal. The validity of primary and secondary end points, i.e. splenic and renal function, and CNS involvement will be ascertained, and the effects of HU on growth, physical and cognitive development in this young cohort will be assessed. Organ evaluations will include splenic scintigraphy and pitted red cell counts; glomerular filtration rate, and evaluation for microalbuminuria and urine concentrating ability; brain MRI/MRA and transcranial doppler (TCD) measurements. This study provides us the unique opportunity for an evaluation of various biomarkers to assess whether HU modulates activation of the circulating cellular elements of blood, and cell-cell interactions, with resulting ameliorative effects on the HbSS infant's vascular pathology and clinical course. Biomarkers to be evaluated will include functional assessment of erythrocyte adhesion to endothelium and to immobilized extra-cellular matrix proteins, F cell numbers, erythrocyte markers including CD71 (stress reticulocyte), various red cell adhesion molecules and phosphatidylserine (PS) positivity. Markers of coagulation activation will include whole blood tissue factor activity (WBTF) and prothrombin fragment F1.2 levels. Endothelial activation will be assessed by plasma sol VCAM-1 and a quantitative and qualitative assessment of circulating endothelial microparticles. Platelet and white cell activation will be evaluated by sol P-selectin and L-selectin levels respectively. We predict that HU therapy, when compared to placebo will result in a pattern of biomarker changes suggestive of a treatment effect. Our evaluations will also provide information delineating the mechanisms by which HU modulates these cell-cell interactions. The two-year follow-up evaluations of clinical course and organ dysfunction in the BABY HUG pilot protocol will also provide us the unique opportunity to assess whether abnormal values of a specific biomarker(s) will predate or occur in conjunction with specific organ dysfunction, or vascular pathology. Large differences will be detectable in these comparisons, while smaller differences will provide the basis for further specimen collection and analysis in the additional 160 children to be later entered in the Phase III Clinical trial. Since our Center possesses significant past experience in biomarker evaluations in infants with HbSS, the incorporation of these appropriately chosen biologic markers to assess disease progression will complement this pilot protocol. Our ancillary proposal should enhance the long-term benefits and scientific productivity of this important multiinstitutional NHLBI-sponsored research. In addition, findings from this study could have significant implications for other disease states associated with vasculopathy.

描述（由申请人提供）：在一项具有里程碑意义的临床试验中，口服羟基脲 (HU) 降低了纯合 SS 病 (HbSS) 成年患者血管闭塞危象和急性胸部综合征的发生频率，并减少了输血和住院治疗的需要。 虽然本研究和其他研究一致认为 HU 在 HbSS 中具有多效性作用模式，对 HbF、致密细胞、网织红细胞、白细胞和红细胞 - 内皮相互作用有影响，但这些单独作用模式在疾病改善方面的相对优点不知道。 NHLBI 将开展一项儿科羟基脲 III 期临床试验 (BABY HUG)，其中 HU 将在一项随机双盲、安慰剂对照试验中进行测试，以预防 200 名 HbSS 婴儿的慢性器官损伤。 作为这项主要研究的前奏，2003 年将对 40 名婴儿（研究开始时年龄为 12 至 17 个月）进行为期两年的 Baby HUG 试点随机安慰剂对照试验，以确定更大规模提案的可行性。 将确定主要和次要终点（即脾功能和肾功能以及中枢神经系统受累）的有效性，并评估 HU 对这一年轻队列的生长、身体和认知发展的影响。 器官评估将包括脾脏闪烁扫描和凹陷红细胞计数；肾小球滤过率、微量白蛋白尿和尿液浓缩能力的评估；脑 MRI/MRA 和经颅多普勒 (TCD) 测量。 这项研究为我们提供了评估各种生物标志物的独特机会，以评估 HU 是否调节血液循环细胞成分的激活以及细胞间相互作用，从而对 HbSS 婴儿的血管病理学和临床病程产生改善作用。 待评估的生物标志物将包括红细胞与内皮和固定的细胞外基质蛋白粘附的功能评估、F细胞数量、红细胞标志物包括CD71（应激网织红细胞）、各种红细胞粘附分子和磷脂酰丝氨酸（PS）阳性。 凝血激活标志物包括全血组织因子活性 (WBTF) 和凝血酶原片段 F1.2 水平。 内皮活化将通过血浆溶胶VCAM-1以及循环内皮微粒的定量和定性评估来评估。 血小板和白细胞的活化将分别通过sol P-选择素和L-选择素水平进行评估。 我们预测，与安慰剂相比，HU 疗法将导致表明治疗效果的生物标志物变化模式。 我们的评估还将提供描述 HU 调节这些细胞间相互作用的机制的信息。 BABY HUG 试点方案中对临床过程和器官功能障碍的两年随访评估也将为我们提供独特的机会来评估特定生物标志物的异常值是否会先于特定器官功能障碍或与特定器官功能障碍同时发生，或血管病理学。 在这些比较中可以检测到较大的差异，而较小的差异将为稍后进入 III 期临床试验的另外 160 名儿童的进一步标本收集和分析提供基础。 由于我们中心过去在 HbSS 婴儿生物标志物评估方面拥有丰富的经验，因此纳入这些适当选择的生物标志物来评估疾病进展将补充该试点方案。 我们的辅助提案应提高 NHLBI 资助的这项重要的多机构研究的长期效益和科学生产力。 此外，这项研究的结果可能对与血管病变相关的其他疾病状态产生重大影响。

项目成果

Phosphatidylserine-positive erythrocytes bind to immobilized and soluble thrombospondin-1 via its heparin-binding domain.

• DOI: 10.1016/j.trsl.2008.07.007
• 发表时间: 2008-10
• 期刊: Translational research : the journal of laboratory and clinical medicine
• 作者: Gayen Betal S;Setty BN
• 通讯作者: Setty BN

Acute kidney injury leads to inflammation and functional changes in the brain.

• DOI: 10.1681/asn.2007080901
• 发表时间: 2008-07
• 期刊: Journal of the American Society of Nephrology : JASN
• 作者: Liu M;Liang Y;Chigurupati S;Lathia JD;Pletnikov M;Sun Z;Crow M;Ross CA;Mattson MP;Rabb H
• 通讯作者: Rabb H