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，包括涉及扩散的白质神经性病变的明显中风，无声的脑梗塞，在对认知障碍和痴呆（VCID）的血管贡献的发病机理中整合了。镰状细胞疾病（SCD）中的一种大量疾病包括影响记忆和高管发挥作用的成年患者的认知能力下降，主要与白质超强度有关。由于镰状血红蛋白聚合而引起的脑微血管的遮挡导致缺氧和随后的重氧（H/R）导致缺血性组织损伤。目前的提案旨在确定脑血管空间内的H/R之间的机械联系，而白质超强度在SCD设置中煽动VCID，从而创建了一个原型，以填补VCID发病机理中的知识差距。使用SCD的临床前小鼠模型，我们发现与正常（AA）小鼠相比，镰刀（SS）小鼠相比，基于磁共振成像的扩散张量成像和组织病理学的微结构白质高强度基本上很丰富。 SS小鼠中的白质高强度与星形胶质细胞的认知下降和激活有关，修饰的神经胶质细胞连接了脑微脉管和神经元。 Frataxin（FXN）是一种负责铁硫簇聚集的线粒体蛋白，可调节星形胶质细胞功能，并与Friedreich的共济失调中的神经变性有关。我们的试点数据表明，在星形胶质细胞中，FXN的表达与缺氧诱导因子1a（HIF-1A）的增加降低，这是H/R事件期间升高的稳态调节转录因子。总体科学假设是，升高的HIF-1A抑制星形胶质细胞frataxin并促进SCD中的白质损伤和VCID。在AIM 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挑战的SS和AA小鼠中的微观结构损伤，神经元钙的积累和星形胶质细胞激活。使用骨髓trasplantation（BMT），我们将评估FXN在缺乏星形胶质细胞FXN表达的镰状嵌合小鼠中H/R损伤后H/R损伤后的白质损伤和认知障碍的作用。在AIM 2中，将使用BMT产生具有星形胶质细胞中HIF-1A靶向缺失的镰刀嵌合体小鼠。新的镰刀嵌合体小鼠将用于确定HIF-1A对于抑制FXN促进白质损伤和认知能力下降是否至关重要。该研究的成功完成将确定FXN是对白质保护的有希望的治疗靶标，这可能有助于为VCID提供弹性。由于SCD中的潜在炎症和缺血通常会加速与年龄相关的病理生理学，因此这项研究将奠定基础，以确定渐进VCID发病机理中缺血和星形胶质细胞功能之间的因果关系，这也有可能使SCD超出SCD的潜力，以使SCD超出SCD，例如常见的混合痴呆症，例如临床上的Alzheimerers病。