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

• 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
• 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

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疾病（SCD）的状态，我们组建了一支由5名主要研究人员组成的团队，其中包括临床研究，免疫学，生物医学工程和微血管成像。我们提出的基础的总体假设是，SCD中组织损伤的严重程度与炎症和血管灌注状态有关。我们的目标是将最小的侵入性技术应用于敏感的评估炎症和微血管闭塞，以分析小鼠和人类SCD：1）患者血液的流式细胞仪测量INKT细胞的激活； 2）对比度增强了超声（CEU），以测量小鼠和人的原位血管体积/灌注。这些是从免疫学和心脏病学领域借用的验证的安全技术。我们将将这些措施与其他疾病指数联系起来，例如人的临床状况以及小鼠的肺功能和插入式显微镜。我们最近发现，可以在小鼠或SCD患者中激活腺苷A2A受体（A2AR）的inkt细胞。我们启动了一项正在进行的临床研究（NIH RC2HL101367），这是由FDA批准的A2AR激动剂的毒品雷达尼森（Regadenoson）的可用性促进的。另一项正在进行的SCD临床试验是评估GMI-1070（一种泛蛋白抑制剂），以减少白细胞粘附于内皮细胞（EC）和血管胶质易粒度发作。为了在更深入的研究中研究白细胞-EC相互作用，我们招募了粘附分子和内内显微镜的权威。为了研究小鼠和人的微血管灌注，我们招募了CEU技术专家，以测量小鼠和人类研究中的血管灌注。数以百万计的患者经历了CEU，以测量心脏和其他组织中的血管灌注。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类研究。这些是雷加德森； GMI-1070;和ATL-801，这是一种临床前A2BR拮抗剂，可抑制RBC病。经过验证后，我们的目标是将这些技术转移到SCD临床试验地点。我们假设，与当前使用的临床结果指标相比，新生物标志物，流式细胞术和CEU的鉴定将是药物有效性的有用指数。此外，这些研究将提供有关触发血管含糊和组织缺血的细胞和分子事件的新信息。 公共卫生相关性：该项目将使用超声来测量组织血管灌注，并将分析来自镰状细胞贫血患者的白细胞。这些程序将为我们提供血流和炎症异常的措施，这些措施将用于更好地理解疾病，并帮助评估新的治疗方法的有效性。