Bronx Comprehensive Sickle Cell Center

布朗克斯综合镰状细胞中心

• 批准号: 6534949
• 负责人: Ronald L Nagel
• 金额: $ 116.33万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6534949
• 关键词: clinical research; cooperative study; sickle cell anemia

DESCRIPTION (provided by applicant): This proposal includes: one clinical Project (Project 2: PI: Dr. Fabry) that builds on the pioneering work of the PI in the last cycle on the development of BOLD-MRI and now near infrared spectroscopy (NIRS) to measure oxygenation perfusion and blood volume in sickle cell patients and novel sickle transgenic mice. The objective is to determine if these state-of-the-art technologies can help in the evaluation of sickle damage to brain, kidney and muscle. In addition, there are three Translational Research projects that aim at finding potentially helpful therapeutic interventions in SCD by the pre-clinical development of several basic research strategies. They are: Project 1 (PI: Dr. Acharya) who is interested in generating a globin chain that has more polymerization inhibitory potential than the paradigmatic HbF, based on the pioneering finding, in the previous cycle, that pig-alpha-chain completely neutralizes human beta5-polymerization. The follow-up is to define the minimum number of pig-alpha-chain sequences that are sufficient to confer the desired properties on the human alpha-globin chain. In the process, we will learn about the quinary structure of sickle polymer as well as the refinement of semisynthesis. Project 3 (PI: Dr. Kaul). also builds on work done in the previous cycle, but the present proposal aims at a quantum leap of knowledge as it pertains to: testing the hypotheses that a heterogenous array of red cell integrins and vWF, P-selectin, laminin, and NO are involved in sickle adhesion, and testing the hypothesis that alphaVBeta3 anionic polysaccharides, and hydroxyurea, can be useful in blocking sickle cell adhesion. Project 4 (PI; Dr. Nagel), builds on a long interest in the multigene involvement in the sickle phenotype. This project aims at defining, by state-of-the art microarray technology, the genes responsible for the pleiotropic effects in sickle cell anemia, as well as which of these have epistatic (modifier) capability to define severity risk and to explore potential epigenetic effects in Beta-gene cluster haplotypes linked to the sickle gene. The projects are supported by an Administrative Core, Transgenic Core (in the forefront of developing sickle animal models), by a micro-CHIP Core (supposed also by our in-house Microarray Facility), a strong Clinical and Patient Services Core, that has pioneered the Day Hospital concept into reality, with the purpose of treating sickle cell anemia patients with uncomplicated painful crises in a way that greatly improves their rate of recovery, their hospitalization rates, and that also favorably affects the in house hospitalization length of stay. This proposal is complemented by two above-the-cap Clinical Project Proposals, both based on last cycle accomplishments.

描述(由申请人提供)： 这项建议包括：一个临床项目(项目2：PI：Dr.Fabry)，该项目建立在PI在上一个周期中关于BOLD-MRI开发的开创性工作的基础上，现在是近红外光谱(NIRS)，用于测量镰状细胞患者和新型镰状转基因小鼠的氧合灌注量和血流量。目的是确定这些最先进的技术是否可以帮助评估镰刀对大脑、肾脏和肌肉的损害。此外，还有三个转化性研究项目，旨在通过几种基本研究策略的临床前开发，寻找对SCD有潜在帮助的治疗干预措施。他们是：项目1(Pi：Dr.Acharya)，他感兴趣的是产生一种比聚合抑制HbF更具聚合抑制潜力的珠蛋白链，这是基于在上一个周期中的开创性发现，即猪的阿尔法链完全中和了人的Beta5聚合。后续工作是定义足以赋予人类α-珠蛋白链所需性质的猪-阿尔法链序列的最小数目。在这个过程中，我们将了解镰刀状聚合物的五元结构以及半合成的精炼。项目3(PI：Kaul博士)。也建立在前一个周期中所做的工作的基础上，但本提案旨在实现知识的巨大飞跃，因为它涉及：测试红细胞整合素和vWF、P-选择素、层粘连蛋白和NO的异质阵列参与镰状细胞黏附的假设，以及测试αVBeta3阴离子多糖和羟基脲在阻断镰状细胞黏附中有用的假说。项目4(Pi；Nagel博士)建立在对多基因参与镰刀表型的长期兴趣的基础上。该项目旨在通过最先进的微阵列技术，确定在镰状细胞性贫血中负责多效性效应的基因，以及这些基因中哪些具有上位性(修饰物)能力来确定严重风险，并探索与镰刀基因连锁的Beta基因簇单倍型的潜在表观遗传效应。这些项目得到了管理核心、转基因核心(处于开发镰刀动物模型的前沿)、微芯片核心(也应该是我们内部的微阵列设施)的支持，这是一个强大的临床和患者服务核心，将日间医院的概念变为现实，目的是以一种极大地提高恢复率、住院率和住院时间的方式治疗患有简单痛苦危机的镰状细胞性贫血患者。这一建议得到了两个高于上限的临床项目建议的补充，这两个建议都是基于上一个周期的成就。