Mechanism of cerebral vaculopathy and stroke in sickle cell disease

镰状细胞病脑血管病和卒中的机制

• 批准号: 9367468
• 负责人: Hyacinth Idu Hyacinth
• 金额: $ 39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-16 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9367468
• 关键词: Adhesions; Age; Age of Onset; Age-Months; Aneurysm; Automobile Driving; Autopsy; Backcrossings; Biological Models; Blood Vessels; Bone Marrow; Brain; Brain imaging; Cell Adhesion Molecules; Cerebral Infarction; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Child; Control Animal; Data; Development; Disease; E-Selectin; Endothelium; Evolution; Genetic; Goals; Growth Factor; Image; Immunohistochemistry; Impaired cognition; Incidence; Individual; Infarction; Integrin alpha4beta1; KDR gene; Knock-out; Knockout Mice; Knowledge; Laser Scanning Microscopy; Learning Disabilities; Leukocytes; Life; Location; Longitudinal Studies; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Measures; Mediating; Modeling; Mus; Outcome; Pathology; Pattern; Pharmacology; Physically Handicapped; Placental Growth Factor; Play; Prevention; Process; Public Health; Research Design; Risk; Role; Sampling; Sickle Cell; Sickle Cell Anemia; Signaling Molecule; Source; Stenosis; Stroke; Stroke prevention; Surface; Testing; Time; Toxic effect; Vascular Cell Adhesion Molecule-1; Vascular Diseases; Vascular remodeling; White Blood Cell Count procedure; angiogenesis; cerebrovascular; imaging platform; in vivo imaging; intervention effect; leukocyte mediator; new therapeutic target; prospective; sickling; spatiotemporal; two-photon

Project Abstract Cerebral infarction (stroke) in sickle cell disease (SCD) is one of the most dramatic and life altering complications of the disease, resulting in physical limitations and potential learning disabilities. Evidence suggests that aberrant leukocyte-endothelial interactions and vascular remodeling might be important contributors to the pathobiology of cerebral vasculopathy and stroke in SCD. Our overall goal is to define the potential role of leukocyte- endothelial adhesion and vascular remodeling in the pathobiological mechanism of cerebral vasculopathy and cerebral infarct in SCD. Identifying molecules with significant role in these pathobiological mechanisms could provide a potentially novel drug target for stroke prevention. In our preliminary data we combined two photon laser scanning microscopy (TPLSM) and MRI/MRA in 12 months old Townes humanized sickle cell mice. This approach enabled us to conduct in vivo imaging documenting the occurrence of abnormal vasodynamic measures (higher RBC velocity and flux), cerebral vasculopathy (vessel tortuosity), and cerebral infarcts in sickle cell compared to control mice. Because our outcomes were spontaneously developing, we are poised to be able to determine the potential factors such as leukocyte-endothelial adhesion and/or aberrant angiogenesis that could be driving the evolution of cerebral vasculopathy and infarction. Our hypothesis is that the spontaneous onset and propagation of cerebral vasculopathy in SCD is due in part to aberrant leukocyte-endothelial interaction and vascular remodeling, mediated by increased endothelial activation and a proangiogenic milieu. Sickle cell mice with genetic or pharmacologic blockade of mediators of leukocyte-endothelial interaction and angiogenesis will be generated and used. These mice will be prospectively imaged alongside appropriate controls using the combination of TPLSM and MRI/MRA for development of cerebral vasculopathy and infarcts. Our specific aims are 1) To determine the spatio-temporal relationship between the presence and/or location of cerebral vasculopathy and incidence, size and number of cerebral infarcts in SCD. This will enable us further validate our model and potentially establish the age of onset for cerebral vasculopathy and infarct in sickle mice. 2) To determine the role of aberrant leukocyte-endothelial interaction in the onset and progression of cerebral vasculopathy and cerebral infarcts. This will allow us to determine whether adhesion molecules already well documented to be associated with known SCD vascular complications are contributors to the pathobiology of cerebral vasculopathy or infarcts and could be potential targets of stroke prevention. 3) To determine the role of vascular endothelial growth factor receptor 2 (VEGFR2) and placenta growth factor (PlGF) in cerebral vascular remodeling, vasculopathy and stroke in SCD. Here we will determine the involvement of angiogenic molecules in the pathobiology of cerebral vasculopathy or infarct in SCD. Also to show whether blocking signaling from these molecules a useful strategy for stroke prevention. Achieving these aims will significantly advance our knowledge of the mechanisms of stroke in SCD.

项目摘要 镰状细胞病（SCD）中的脑梗死（卒中）是最引人注目和改变生命的并发症之一 这种疾病导致身体限制和潜在的学习障碍。有证据表明， 白细胞-内皮细胞相互作用和血管重塑可能是病理生物学的重要贡献者 脑血管病和中风的风险。我们的总体目标是确定白细胞的潜在作用- 内皮细胞粘附和血管重塑在脑血管病病理生物学机制中的作用， SCD脑梗死。鉴定在这些病理生物学机制中具有重要作用的分子， 为预防中风提供了一个潜在的新型药物靶点。在我们的初步数据中， 激光扫描显微镜（TPLSM）和MRI/MRA。这 这种方法使我们能够进行体内成像，记录血管动力学异常的发生。 测量（较高的红细胞速度和流量），脑血管病（血管迂曲），和脑梗死的镰状细胞 与对照小鼠相比。因为我们的成果是自发发展的，我们准备能够 以确定潜在的因素，如白细胞-内皮细胞粘附和/或异常血管生成， 可能会导致脑血管病和脑梗死的发展我们的假设是自发的 SCD中脑血管病变的发生和发展部分是由于异常的白细胞-内皮细胞 相互作用和血管重塑，通过增加内皮活化和促血管生成 环境。白细胞-内皮细胞相互作用介质的遗传或药物阻断的镰状细胞小鼠 并且血管生成将被产生和使用。这些小鼠将与适当的 对照组使用TPLSM和MRI/MRA的组合用于脑血管病和梗死的发展。 我们的具体目标是1）确定存在和/或 SCD患者脑血管病变的部位与脑梗死的发生率、面积和数目。这将 使我们能够进一步验证我们的模型，并可能建立脑血管病的发病年龄， 镰状小鼠梗死。2)确定异常白细胞-内皮细胞相互作用在原发性高血压发病中的作用， 以及脑血管病和脑梗死的进展。这将使我们能够确定 已经有充分证据证明与已知SCD血管并发症相关的粘附分子， 脑血管病或梗死的病理生物学的贡献者，并可能是中风的潜在目标 预防3)为了确定血管内皮生长因子受体2（VEGFR 2）和 胎盘生长因子（PlGF）在SCD脑血管重构、血管病变和卒中中的作用。这里我们 将确定血管生成分子在脑血管病或脑梗死病理生物学中的参与， SCD。还为了表明阻断这些分子的信号传导是否是预防中风的有用策略。 这些目标的实现将大大提高我们对SCD卒中机制的认识。