Neurovascular frataxin and cognitive dysfunction in sickle cell disease

镰状细胞病中的神经血管 frataxin 和认知功能障碍

基本信息

批准号：
10810463
负责人：
Rimi Hazra
金额：
$ 23.08万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-25 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10810463
关键词：
Acceleration Acute Adult Affect Alzheimer&apos s Disease Anisotropy Area Astrocytes Behavioral Biochemical Biogenesis Biological Assay Blood Vessels Blood flow Bone Marrow Bone Marrow Transplantation Brain Calcium Cells Cerebral Hypoxia Cerebral Infarction Cerebral Ischemia Cerebrovascular system Cerebrum Chimera organism Clinical Clinical Research Cognitive Data Development Diffusion Diffusion Magnetic Resonance Imaging Discrimination Doxorubicin Event Exhibits Exposure to Foundations Friedreich Ataxia Functional disorder Future Glial Fibrillary Acidic Protein Health Hemoglobin Hemolysis Histopathology Homeostasis Human Hypoxemia Hypoxia Hypoxia Inducible Factor Immunofluorescence Immunologic Impaired cognition Individual Inflammation Injury Iron Ischemia Knock-out Knowledge Lesion Link Magnetic Resonance Imaging Memory Mitochondria Mitochondrial Proteins Mouse Strains Mus Mutate Myelin Basic Proteins Nerve Degeneration Neurofilament-H Neuroglia Neurons Pathogenesis Pathway interactions Patients Phenocopy Prevention Proteins Research Role Short-Term Memory Sickle Cell Anemia Sickle Hemoglobin Small Interfering RNA Stains Stroke Sulfur Testing Therapeutic Tissues Transgenic Organisms Transplantation White Matter Hyperintensity Wild Type Mouse age related axon injury burden of illness cerebral microvasculature cerebrovascular cerebrovascular lesion cognitive function cognitive testing executive function experience experimental study frataxin hemoglobin polymer improved indexing innovation insight mixed dementia mouse model neurovascular new therapeutic target novel object recognition pre-clinical processing speed prototype resilience restoration sickling spatial memory therapeutic target transcription factor vascular cognitive impairment and dementia white matter white matter injury

项目摘要

Cerebrovascular injuries, including overt stroke, silent cerebral infarction involving diffused white matter neuroaxonal lesions are integrated within the pathogenesis of vascular contributions to cognitive impairment and dementia (VCID). A significant disease burden in sickle cell disease (SCD) includes cognitive decline affecting >50% of the adult patients impacting memory and executive functioning primarily associated with white matter hyperintensities. Occlusions of the cerebral microvessels due to sickle hemoglobin polymerization results in hypoxia and subsequent reoxygenation (H/R) leading to ischemic tissue damage. The present proposal, set to determine the mechanistic link between H/R within the cerebrovascular space and the white matter hyperintensities instigating VCID in SCD setting, thus create a prototype to fill the knowledge gap in the pathogenesis of VCID. Using a preclinical mouse model of SCD, we found that microstructural white matter hyperintensities, identified by magnetic resonance imaging-based diffusion tensor imaging and histopathology are substantially abundant in sickle (SS) mice compared to normal (AA) mice. The white matter hyperintensities in the SS mice were associated with cognitive decline and activation of astrocytes, the modified glial cells connecting cerebral microvasculature and the neurons. Frataxin (FXN), a mitochondrial protein responsible for iron-sulfer clustering, regulates astrocyte function and is associated with neurodegeneration in Friedreich’s ataxia. Our pilot data showed that expression of FXN is reduced in the astrocytes concomitant with an increase in hypoxia inducible factor-1a (HIF-1a), a homeostatic regulatory transcription factor that is elevated during H/R events. The overarching scientific hypothesis is that elevated HIF-1a inhibits astrocytic frataxin and promotes white matter injury and VCID in SCD. In Aim 1, we will be performing diffusion tensor imaging and immunofluorescence experiments to assess microstructural damage, neuronal calcium accumulation and astrocyte activation in H/R-challenged SS and AA mice. Using bone marrow trasplantation (BMT), we will be assessing the role of FXN in the development of white matter injury and cognitive impairment following H/R injury in the sickle chimera mice lacking expression of astrocytic FXN. In Aim 2, a sickle chimera mice with targeted deletion of HIF-1a in the astrocytes will be generated using BMT. The new sickle chimera mice will be used to determine whether HIF-1a is critical for inhibition of FXN promoting white matter injury and cognitive decline. Successful completion of the study will identify FXN as a promising therapeutic target for white matter protection that may help provide resilience against VCID. Since underlying inflammation and ischemia often accelerate age-related pathophysiology in SCD, this study will lay the foundation to identify the causal link between ischemia and astrocyte function in the pathogenesis of progressive VCID, which also has the potential to generalize beyond VCID in SCD to common mixed dementias such as clinical Alzheimer’s disease.

脑血管损伤，包括明显的中风、涉及弥漫性白质神经轴突病变的无症状脑梗塞，与血管导致认知障碍和痴呆 (VCID) 的发病机制相结合，镰状细胞病 (SCD) 的一个重要疾病负担包括影响 > 50 的认知能力下降。影响记忆和执行功能的成年患者的百分比主要与白质高信号有关，镰状血红蛋白聚合导致脑微血管闭塞，导致缺氧和随后的症状。本提案旨在确定脑血管间隙内的 H/R 与 SCD 环境中引发 VCID 的白质高信号之间的机制联系，从而创建一个原型来填补知识空白。使用 SCD 的临床前小鼠模型，我们发现通过基于磁共振成像的弥散张量成像识别出微结构白质高信号。与正常（AA）小鼠相比，镰状（SS）小鼠的白质高信号与星形胶质细胞（连接脑微血管和神经元的修饰神经胶质细胞）的认知衰退和激活有关。），一种负责铁硫簇的线粒体蛋白，调节星形胶质细胞功能并与弗里德赖希共济失调中的神经变性相关。我们的试验数据表明 FXN 的表达是星形胶质细胞中的 HIF-1a 减少，同时缺氧诱导因子 1a (HIF-1a) 增加，HIF-1a 是一种稳态调节转录因子，在 H/R 事件期间升高。总体科学假设是，升高的 HIF-1a 会抑制星形细胞 frataxin 并促进白色。 SCD 中的物质损伤和 VCID 在目标 1 中，我们将进行扩散张量成像和免疫荧光实验来评估微观结构损伤、神经钙积累和H/R 攻击的 SS 和 AA 小鼠中的星形胶质细胞激活，我们将使用骨髓移植 (BMT) 评估 FXN 在缺乏 H/R 损伤的镰状嵌合体小鼠中白质损伤和认知障碍发展中的作用。在目标 2 中，将使用 BMT 生成星形胶质细胞中定向删除 HIF-1a 的镰状嵌合体小鼠。小鼠将被用来确定 HIF-1a 是否对于抑制 FXN 促进白质损伤和认知能力下降至关重要。该研究的成功完成将确定 FXN 是一种有前途的白质保护治疗靶点，可能有助于提供针对 VCID 的恢复能力。潜在的炎症和缺血往往会加速 SCD 中与年龄相关的病理生理学，这项研究将为确定进行性 VCID 发病机制中缺血和星形胶质细胞功能之间的因果关系奠定基础，该研究也有可能推广到其他领域SCD 中的 VCID 到常见的混合性痴呆，如临床阿尔茨海默病。