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: 10385286
• 负责人: Hyacinth Idu Hyacinth
• 金额: $ 40.5万
• 依托单位: UNIVERSITY OF CINCINNATI
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385286
• 关键词: Adhesions; Age of Onset; Age-Months; Aneurysm; Automobile Driving; Autopsy; Backcrossings; Biological Models; Blood Flow Velocity; Bone Marrow; Brain; Brain imaging; Cell Adhesion Molecules; Cerebral Infarction; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; 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; P-Selectin; PGF gene; Pathology; Pattern; Pharmacology; Play; Prevention; Process; Public Health; Research Design; 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 Endothelial Growth Factors; Vascular remodeling; White Blood Cell Count procedure; angiogenesis; cerebrovascular; imaging platform; in vivo imaging; intervention effect; leukocyte mediator; new therapeutic target; physically handicapped; prospective; sickling; spatiotemporal; stroke risk; two-photon; vaso-occlusive crisis

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 镰状细胞疾病（SCD）中的脑梗塞（中风）是最引人注目，改变生命的并发症之一 疾病，导致身体局限性和潜在的学习障碍。证据表明异常 白细胞 - 内皮相互作用和血管重塑可能是病原体的重要因素 SCD中的大脑血管病和中风我们的总体目标是确定白细胞的潜在作用 脑血管病的病理生物学机制中的内皮粘附和血管重塑 SCD中的脑梗塞。在这些病理生物学机制中识别具有重要作用的分子可以 为预防中风提供了潜在的新型药物靶标。在我们的初步数据中，我们合并了两个光子 在12个月大的城镇中，激光扫描显微镜（TPLSM）和MRI/MRA人为镰状细胞小鼠。这 方法使我们能够进行体内成像，以记录异常血管动力学的发生 措施（较高的RBC速度和通量），脑血管病（骨折）和镰状脑梗塞 与对照小鼠相比细胞。因为我们的结果是自发发展的，所以我们有能力 确定潜在因素，例如白细胞 - 内皮粘附和/或异常血管生成 可能会推动脑血管病和梗死的演变。我们的假设是自发 SCD中大脑血管病的发作和繁殖部分是由于白细胞 - 内皮异常 相互作用和血管重塑，由内皮激活增加和促血管生成介导 环境。镰状细胞小鼠具有白细胞 - 内皮相互作用介体的遗传或药理阻滞 将生成和使用血管生成。这些老鼠将与适当的前瞻性成像 使用TPLSM和MRI/MRA组合的对照来发展脑血管病和梗塞。 我们的具体目的是1）确定存在与/或之间的时空关系 SCD中脑血管病和发病率，大小和脑梗塞数量的位置。这会 使我们能够进一步验证我们的模型，并有可能建立脑血管病和 在镰状小鼠中梗塞。 2）确定异常白细胞 - 内皮相互作用在发作中的作用 脑血管病和脑梗塞的进展。这将使我们能够确定是否 粘附分子已经有充分的文献证明与已知的SCD血管并发症有关 脑血管病或梗死的病理学的贡献者，可能是中风的潜在靶标 预防。 3）确定血管内皮生长因子受体2（VEGFR2）和 SCD中的脑血管重塑，血管病和中风中的胎盘生长因子（PLGF）。我们在这里 将确定血管生成分子参与脑血管病变或梗死的病理生物学 scd。还可以证明从这些分子中阻断信号是否是预防中风的有用策略。 实现这些目标将大大提高我们对SCD中风机制的了解。