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

• 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
• 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' 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

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索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) 的一个重大疾病负担包括认知能力下降，影响超过 50% 的成年患者，影响记忆和执行功能，主要与白质高信号相关。镰状血红蛋白聚合导致脑微血管闭塞，导致缺氧和随后的复氧（H/R），从而导致缺血性组织损伤。目前的提议旨在确定脑血管内的 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 VCID 发病机制的知识空白。使用 SCD 的临床前小鼠模型，我们发现与正常 (AA) 小鼠相比，通过基于磁共振成像的扩散张量成像和组织病理学鉴定的微结构白质高信号在镰状 (SS) 小鼠中显着丰富。 SS 小鼠的白质高信号与认知能力下降和星形胶质细胞（连接大脑微血管和神经元的修饰神经胶质细胞）的激活有关。 Frataxin (FXN) 是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有关。我们的试验数据表明，星形胶质细胞中 FXN 的表达减少，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。最重要的科学假设是，HIF-1a 升高会抑制星形细胞 frataxin，并促进 SCD 中的白质损伤和 VCID。在目标 1 中，我们将进行扩散张量成像和免疫荧光实验，以评估 H/R 攻击的 SS 和 AA 小鼠的微观结构损伤、神经元钙积累和星形胶质细胞活化。使用骨髓移植 (BMT)，我们将评估 FXN 在缺乏星形胶质细胞 FXN 表达的镰状嵌合体小鼠 H/R 损伤后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。新的镰状嵌合体小鼠将用于确定 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，可能有助于增强抵抗 VCID 的能力。由于潜在的炎症和缺血通常会加速 SCD 中与年龄相关的病理生理学，因此这项研究将为确定缺血和星形胶质细胞功能在进行性 VCID 发病机制中的因果关系奠定基础，这也有可能将 SCD 中的 VCID 推广到常见的混合性痴呆，例如临床阿尔茨海默病。