Humanin and Intracerebral Hemorrhage

护脑素与脑出血

• 批准号: 10547749
• 负责人: Jaroslaw Aronowski
• 金额: $ 47.05万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547749
• 关键词: Acute; Affect; Age; Alzheimer' s Disease; Animal Model; Anti-Inflammatory Agents; Apoptotic; Astrocytes; Attenuated; Autologous; Biology; Blood; Brain; Brain Injuries; Cell Culture System; Cells; Cerebral hemisphere hemorrhage; Cerebrovascular Disorders; Cessation of life; Cognitive deficits; Cytoprotection; Edema; Etiology; Exposure to; FDA approved; Female; Gene Expression; Gene Targeting; Genome; Glial Fibrillary Acidic Protein; Goals; Hematoma; Hemin; Histologic; Immunohistochemistry; In Vitro; Inflammation; Inflammatory Response; Injections; Injury; Intravenous; Ischemic Stroke; Knockout Mice; Label; Lead; Longevity; Macrophage; Measures; Mediating; Microglia; Mitochondria; Mitochondrial DNA; Modeling; Morbidity - disease rate; Motor; Mus; Nervous System Trauma; Neurites; Neurologic; Neurologic Deficit; Neurologic Dysfunctions; Neuronal Plasticity; Neurons; Outcome; Oxidative Stress; Patients; Peptides; Phagocytes; Phagocytosis; Phenotype; Play; Production; RNA, Ribosomal, 16S; Recombinants; Resistance; Resolution; Rodent; Role; SOD2 gene; STAT3 gene; Secure; Sensory; Sex Differences; Sorting; Stroke; Surface; Testing; Therapeutic Effect; Translating; Treatment Efficacy; Up-Regulation; Work; age related; aged; aging population; biological adaptation to stress; blood product; cerebral atrophy; clinically relevant; collagenase; disability; effective therapy; experimental study; healing; humanin; improved; in vitro Model; in vivo; indexing; inhibitor; injured; knock-down; male; morphometry; mortality; neuron loss; novel; overexpression; oxidative damage; pharmacologic; protective effect; pup; receptor; receptor expression; repaired; response; restoration; stressor; therapeutic target; transcription factor

ABSTRACT Intracerebral hemorrhage (ICH) is the most devastating subtype of stroke with high mortality rates, and profound morbidity and disability. The mechanisms leading to brain damage caused by ICH are multifaceted and poorly understood. There is no FDA approved treatment for ICH. Recent studies and our preliminary work indicate that astrocytes, cells known to have a uniquely dense network of mitochondria (Mt), secrete intact Mt, which upon entering adjacent neurons or microglia could help them resist injury and promote restorative function when exposed to the damage effects of intracerebral blood products. While the biology of Mt transfer is seen as homeostatic, the mechanisms behind their beneficial effect is unclear. One of the unique functions of Mt is to produce, from its own genome, a small potent bioactive secretory peptide, humanin (HN; encoded in the Mt DNA 16S ribosomal RNA region), which acts through a specific surface receptor present in the brain, including on neurons and microglia. HN is implicated in Mt-associated longevity and has cytoprotective activities. However, the mechanism behind these beneficial effects of HN in cerebrovascular diseases and its clinical relevance remains unclear. Our extensive preliminary results demonstrate: (1) a robust Mt transfer from astrocytes to neurons or to microglia and that the transfer confers cytoptotection in neurons and a “healing” phenotype in microglia under ICH-like conditions. (2) ICH-mediated injury in mice results in a profound loss of HN in the ICH-affected hemisphere and treatment with recombinant HN (rHN) significantly reduced neurological deficits produced by ICH. (3) HN or astrocytic Mt-transfer into neurons leads to (a) STAT3/MnSOD upregulation and reduction of oxidative damage to neurons, and (b) PPAR upregulation in microglia and a “healing” phenotype, including increased phagocytic capacity. Therefore, we hypothesize that Mt-derived HN, released or transferred within the intact Mt secreted from astrocytes (or injected as recombinant HN, rHN) can reduce ICH-mediated damage (1) by increasing neuronal resistance to oxidative damage (through upregulating Mt anti-oxidative Mn-SOD) and by supporting neural plasticity; and (2) by securing “healing” (phagocytic/anti-oxidative/anti-inflammatory/trophic) phenotype of microglia, through transcription factor PPAR. Our specific aims are: (1) To establish (in vitro) the cellular mechanisms by which astrocytic HN and Mt transfer (A) attenuates injury to neurons and (B) promotes the “healing” phenotype to microglia under conditions simulating ICH. (2) To determine (in vivo) the translational value and mechanism by which Mt/HN mediates protection from damage imposed by ICH. (3) To establish age/sex-related differences in Mt transfer, and HN expression by using aged male and female mice, and the therapeutic effect of HN in ICH.

摘要 脑出血(ICH)是最具破坏性的卒中亚型，死亡率高，且 严重的发病率和致残率。脑出血导致脑损伤的机制是多方面的。 也很难被理解。目前还没有FDA批准的治疗脑出血的方法。 最近的研究和我们的初步工作表明，星形胶质细胞，即已知具有独特致密网络的细胞 线粒体(Mt)，分泌完整的mt，当它们进入邻近的神经元或小胶质细胞时，可以帮助它们抵抗 当暴露于脑内血液制品的损害作用时，可促进损伤和恢复功能。 虽然mt转移的生物学机制被认为是动态平衡的，但其有益效果背后的机制尚不清楚。 Mt的独特功能之一是从它自己的基因组中产生一种小的、有效的生物活性分泌肽， 人蛋白(HN；编码在线粒体DNA 16S核糖体RNA区域)，通过特定的表面受体起作用 存在于大脑中，包括神经元和小胶质细胞。HN与多发性硬化症相关的长寿有关，并 细胞保护活性。然而，HN在脑血管中的这些有益作用背后的机制 疾病及其临床相关性仍不清楚。 我们广泛的初步结果表明：(1)星形胶质细胞向神经元或小胶质细胞转移mt的能力很强。 在ICH样下，这种转移给予神经元细胞保护和小胶质细胞的“愈合”表型。 条件。(2)脑出血致小鼠脑出血所致大脑半球HN严重丢失。 重组HN(RHN)治疗可显著减少脑出血所致的神经功能缺失。(3)HN或 星形胶质细胞线粒体向神经元的转移导致(A)STAT3/MnSOD上调和氧化损伤减轻 (B)小胶质细胞中PPAR表达上调，以及包括吞噬细胞增加在内的“愈合”表型 容量。 因此，我们假设mt来源的HN在完整的mt内释放或转移是从 星形胶质细胞(或作为重组HN、RHN注射)可通过增加神经元数量来减少脑出血介导的损伤(1) 抗氧化性损伤(通过上调线粒体抗氧化性锰-超氧化物歧化酶)和支持神经 可塑性；以及(2)通过确保(phagocytic/anti-oxidative/anti-inflammatory/trophic)表型的“修复” 小胶质细胞，通过转录因子PPAR。 我们的具体目标是：(1)(在体外)建立星形细胞HN和mt转移的细胞机制 (A)减轻对神经元的损伤；(B)在条件下促进小胶质细胞的“愈合”表型 模拟脑出血。(2)(体内)确定mt/hn的翻译价值和机制 保护免受非物质文化遗产的损害。(3)建立与年龄/性别相关的MT转移和HN的差异 老年雄性和雌性小鼠的表达，以及HN对脑出血的治疗作用。

项目成果

Transplantation of Astrocytic Mitochondria Modulates Neuronal Antioxidant Defense and Neuroplasticity and Promotes Functional Recovery after Intracerebral Hemorrhage.

星形细胞线粒体移植可调节神经元抗氧化防御和神经可塑性，并促进脑出血后的功能恢复。

• DOI: 10.1523/jneurosci.2222-21.2022
• 发表时间: 2022
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Tashiro,Ryosuke;Bautista-Garrido,Jesus;Ozaki,Dan;Sun,Guanghua;Obertas,Lidiya;Mobley,AlexisS;Kim,GabSeok;Aronowski,Jaroslaw;Jung,JooEun
• 通讯作者: Jung,JooEun