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

基本信息

批准号：
10394156
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
项目类别：
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/10394156
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

项目摘要

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) 中的脑梗塞（中风）是最严重且改变生活的并发症之一该疾病导致身体限制和潜在的学习障碍。有证据表明，异常白细胞-内皮相互作用和血管重塑可能是病理生物学的重要贡献者 SCD 中的脑血管病变和中风。我们的总体目标是确定白细胞的潜在作用脑血管病病理生物学机制中的内皮粘附和血管重塑 SCD 中的脑梗塞。识别在这些病理生物学机制中具有重要作用的分子可以为预防中风提供了一个潜在的新药物靶点。在我们的初步数据中，我们结合了两个光子 12 个月大的 Townes 人源化镰状细胞小鼠的激光扫描显微镜 (TPLSM) 和 MRI/MRA。这该方法使我们能够进行体内成像，记录异常血管动力学的发生措施（较高的红细胞速度和流量）、脑血管病变（血管迂曲）和镰刀型脑梗塞细胞与对照小鼠相比。因为我们的结果是自发发展的，所以我们准备能够确定潜在因素，例如白细胞-内皮粘附和/或异常血管生成可能正在推动脑血管病变和梗塞的发展。我们的假设是自发的 SCD 中脑血管病变的发生和传播部分是由于白细胞内皮细胞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。对白细胞-内皮相互作用介质进行遗传或药理学阻断的镰状细胞小鼠血管生成将被产生和使用。这些小鼠将与适当的小鼠一起进行前瞻性成像结合使用 TPLSM 和 MRI/MRA 来控制脑血管病变和梗塞的发展。我们的具体目标是 1）确定存在和/或之间的时空关系 SCD 中脑血管病变的部位以及脑梗塞的发生率、大小和数量。这将使我们能够进一步验证我们的模型并有可能确定脑血管病的发病年龄和镰状小鼠的梗塞。 2) 确定异常白细胞-内皮相互作用在发病中的作用以及脑血管病变和脑梗塞的进展。这将使我们能够确定是否已被充分证明与已知 SCD 血管并发症相关的粘附分子是脑血管病或梗塞的病理学贡献者，可能是中风的潜在目标预防。 3）确定血管内皮生长因子受体2（VEGFR2）的作用和胎盘生长因子 (PlGF) 在 SCD 脑血管重塑、血管病变和中风中的作用。在这里我们将确定血管生成分子在脑血管病或梗死的病理学中的参与 SCD。还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。实现这些目标将显着增进我们对 SCD 中风机制的了解。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The inflammatory profiles of pulmonary alveolar macrophages and alveolar type 2 cells in SCD.

SCD 中肺泡巨噬细胞和肺泡 2 型细胞的炎症特征。

DOI：
发表时间：
2023-06
期刊：
影响因子：
0
作者：
Gbotosho, Oluwabukola T;Li, Wei;Joiner, Clinton H;Brown, Lou Ann S;Hyacinth, Hyacinth I
通讯作者：
Hyacinth, Hyacinth I

Factors associated with decreased survival from neonatal malaria infection in Jos, North Central Nigeria.

尼日利亚中北部乔斯市新生儿疟疾感染存活率下降的相关因素。

DOI：
发表时间：
2011-07
期刊：
影响因子：
0
作者：
Yilgwan, Christopher S;Hyacinth, Hyacinth I;Oguche, Stephen
通讯作者：
Oguche, Stephen

Adhesion molecules and cerebral microvascular hemodynamic abnormalities in sickle cell disease.

镰状细胞病中的粘附分子和脑微血管血流动力学异常。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Abi Rached, Noor Mary;Gbotosho, Oluwabukola T;Archer, David R;Jones, Jayre A;Sterling, Morgan S;Hyacinth, Hyacinth I
通讯作者：
Hyacinth, Hyacinth I

Neuroinflammation underlies the development of social stress induced cognitive deficit in sickle cell disease.

神经炎症是镰状细胞病中社会压力诱发认知缺陷发展的基础。

DOI：
发表时间：
2024-01-25
期刊：
影响因子：
0
作者：
DeVeaux, S'Dravious A;Vyshnya, Sofiya;Propsom, Katherine;Gbotosho, Oluwabukola T;Singh, Asem S;Horning, Robert Z;Sharma, Mihika;Jegga, Anil G;Niu, Liang;Botchwey, Edward A;Hyacinth, Hyacinth I
通讯作者：
Hyacinth, Hyacinth I

An Investigation of the Antioxidant Capacity in Extracts from Moringa oleifera Plants Grown in Jamaica.

牙买加辣木植物提取物抗氧化能力的研究。

DOI：
发表时间：
2017-10-23
期刊：
影响因子：
0
作者：
Wright, Racquel J;Lee, Ken S;Hyacinth, Hyacinth I;Hibbert, Jacqueline M;Reid, Marvin E;Wheatley, Andrew O;Asemota, Helen N
通讯作者：
Asemota, Helen N