Biomarkers of Inflammation and Vaso-occlusion in Sickle Cell Disease

镰状细胞病炎症和血管闭塞的生物标志物

基本信息

批准号：
8222685
负责人：
Joshua Jeffrey Field
金额：
$ 90.42万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8222685
关键词：
Adenosine A2A Receptor Adhesions Agonist Biological Markers Biology Biomedical Engineering Blood Blood Cells Blood Flow Cytometry Blood Vessels Blood flow Cardiology Cell Adhesion Molecules Cell Communication Cells Clinical Clinical Investigator Clinical Trials Collaborations Cytolysis Data Disease Effectiveness Endothelial Cells Event FDA approved Flow Cytometry Functional disorder Goals Heart Human Image Immunology In Situ Inflammation Injury Ischemia Kidney Leg Leukocytes Lung Measures Methods Molecular Monitor Mus Outcome Measure Pain Pathology Patients Perfusion Persons Pharmaceutical Preparations Pilot Projects Principal Investigator Procedures Recruitment Activity Regulatory Pathway Research Personnel Respiratory physiology Selectins Severities Sickle Cell Sickle Cell Anemia Site Techniques Therapeutic Thrombosis Tissues Transfusion Treatment Efficacy Ultrasonography United States National Institutes of Health Vision Work authority base cremaster muscle drug candidate improved in vivo indexing inhibitor/antagonist intravital microscopy meetings minimally invasive novel therapeutic intervention pre-clinical pulmonary function receptor response vascular inflammation vaso-occlusive pain

项目摘要

DESCRIPTION (provided by applicant): In order to identify new biomarkers to assess the status of patients with sickle cell disease (SCD) we have assembled a team of 5 principal investigators with expertise encompassing clinical investigation, immunology, biomedical engineering and microvascular imaging. The overarching hypothesis underlying our proposal is that the severity of tissue injury in SCD is related to the state of inflammation and vascular perfusion. Our goals are to apply minimally invasive techniques for sensitively assessing inflammation and microvascular occlusion to the analysis of mouse and human SCD: 1) flow cytometry of patient blood to measure iNKT cell activation; and 2) contrast enhanced ultrasound (CEU) to measure vascular volume/perfusion in situ in mice and people. These are validated safe techniques borrowed from the fields of immunology and cardiology. We will relate these measures to other disease indices such as clinical status in people and pulmonary function and intravital microscopy in mice. We recently discovered that iNKT cells, which can be inhibited by activation of adenosine A2A receptors (A2ARs), are activated in mice or persons with SCD. We initiated an ongoing clinical investigation (NIH RC2HL101367) facilitated by the availability of the drug regadenoson, an FDA approved A2AR agonist. Another ongoing SCD clinical trial is evaluating GMI-1070, a pan-selectin inhibitor, to reduce leukocyte adhesion to endothelial cells (EC) and vaso-occlusive episodes. To study leukocyte-EC interactions in greater depth we recruited an authority on adhesion molecules and intravital microscopy. In order to study microvascular perfusion in mice and people we recruited an expert in the technique of CEU to measure vascular perfusion in mouse and human studies. Millions of patients have undergone CEU to measure vascular perfusion in heart and other tissues. These methods will be used to assess three SCD drug candidates in mice and when possible, human studies. These are regadenoson; GMI- 1070; and ATL-801, a preclinical A2BR antagonist that inhibits RBC sickling. After they are validated, our goal is to transfer these techniques to SCD clinical trial sites. We hypothesize that the identification of new biomarkers, flow cytometric and CEU, will be more useful indices of drug effectiveness than currently used clinical outcome measures. In addition, these studies will provide new information about the cellular and molecular events that trigger vaso-occlusion and tissue ischemia in SCD. PUBLIC HEALTH RELEVANCE: This project will use ultrasound to measure tissue vascular perfusion, and will analyze white blood cells from patients with sickle cell anemia. These procedures will provide us with measures of abnormalities in blood flow and inflammation that will be used to better understand the disease, and also to help evaluate the effectiveness of new therapeutic approaches.

描述（由申请人提供）：为了确定新的生物标志物来评估镰状细胞病 (SCD) 患者的状况，我们组建了一个由 5 名主要研究人员组成的团队，他们的专业知识涵盖临床研究、免疫学、生物医学工程和微血管成像。我们提议的总体假设是，SCD 中组织损伤的严重程度与炎症和血管灌注状态有关。我们的目标是将灵敏评估炎症和微血管闭塞的微创技术应用于小鼠和人类 SCD 的分析：1) 对患者血液进行流式细胞术以测量 iNKT 细胞活化； 2) 对比增强超声 (CEU) 用于测量小鼠和人的原位血管容量/灌注。这些是从免疫学和心脏病学领域借鉴的经过验证的安全技术。我们将把这些措施与其他疾病指标联系起来，例如人类的临床状态和小鼠的肺功能和活体显微镜检查。我们最近发现，可通过腺苷 A2A 受体 (A2AR) 的激活来抑制的 iNKT 细胞在患有 SCD 的小鼠或人体内被激活。我们启动了一项正在进行的临床研究 (NIH RC2HL101367)，该研究是由 FDA 批准的 A2AR 激动剂 regadenoson 药物的上市推动的。另一项正在进行的 SCD 临床试验正在评估 GMI-1070（一种全选择素抑制剂），以减少白细胞与内皮细胞 (EC) 的粘附和血管闭塞事件。为了更深入地研究白细胞-EC 相互作用，我们聘请了粘附分子和活体显微镜方面的权威。为了研究小鼠和人类的微血管灌注，我们聘请了 CEU 技术专家来测量小鼠和人类研究中的血管灌注。数百万患者接受了 CEU 来测量心脏和其他组织的血管灌注。这些方法将用于评估小鼠中的三种 SCD 候选药物，并在可能的情况下进行人体研究。这些是热加腺苷； GMI-1070；和 ATL-801，一种抑制红细胞镰状化的临床前 A2BR 拮抗剂。经过验证后，我们的目标是将这些技术转移到 SCD 临床试验场所。我们假设新的生物标志物、流式细胞术和 CEU 的鉴定将是比目前使用的临床结果测量更有用的药物有效性指标。此外，这些研究将提供有关 SCD 中引发血管闭塞和组织缺血的细胞和分子事件的新信息。公共健康相关性：该项目将使用超声波测量组织血管灌注，并将分析镰状细胞性贫血患者的白细胞。这些程序将为我们提供血流异常和炎症的测量方法，用于更好地了解这种疾病，并帮助评估新治疗方法的有效性。