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，包括显性中风，无症状脑梗死涉及弥漫性白色物质神经轴索病变是整合在血管的认知功能障碍和痴呆（VCID）的发病机制。镰状细胞病（SCD）的显著疾病负担包括影响>50%的成年患者的认知下降，其影响主要与白色物质高信号相关的记忆和执行功能。由于镰状血红蛋白聚合导致的脑微血管闭塞导致缺氧和随后的再氧合（H/R），从而导致缺血性组织损伤。本提案旨在确定脑血管空间内的H/R与SCD环境中引发VCID的白色高信号之间的机制联系，从而创建一个原型以填补VCID发病机制中的知识空白。使用SCD的临床前小鼠模型，我们发现，微结构白色物质高信号，确定磁共振成像为基础的扩散张量成像和组织病理学是相当丰富的镰刀（SS）小鼠相比，正常（AA）小鼠。SS小鼠的白色高信号与认知能力下降和星形胶质细胞的激活有关，星形胶质细胞是连接脑微血管和神经元的修饰的胶质细胞。Frataxin（FXN）是一种负责铁硫聚集的线粒体蛋白，调节星形胶质细胞功能，并与Friedreich共济失调中的神经变性相关。我们的试验数据表明，FXN的表达减少，伴随着缺氧诱导因子-1a（HIF-1a）的增加，缺氧诱导因子-1a（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，升高的HIF-1 α抑制星形细胞共济失调蛋白，促进SCD中的白色物质损伤和VCID。在目标1中，我们将进行扩散张量成像和免疫荧光实验，以评估H/R激发的SS和AA小鼠的微结构损伤，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中H/R损伤后白色损伤和认知障碍的发展中的作用。在目标2中，将使用BMT产生星形胶质细胞中具有靶向缺失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-1 a是否对抑制FXN促进白色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作为白色保护的有希望的治疗靶点，可能有助于提供对VCID的恢复力。由于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，因此本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，这也有可能将SCD中的VCID推广到常见的混合性痴呆，如临床阿尔茨海默病。