Humanin and Intracerebral Hemorrhage

护脑素与脑出血

• 批准号: 10316990
• 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/10316990
• 关键词: Acute; Affect; 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; 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; Knockout Mice; Label; Lead; Longevity; 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; Peroxisome Proliferator-Activated Receptors; Phagocytes; Phagocytosis; Pharmacology; Phenotype; Play; Production; RNA, Ribosomal, 16S; Recombinants; Resistance; Resolution; Rodent; Role; SOD2 gene; STAT3 gene; Secure; Sensory; Sex Differences; Stroke; Surface; Testing; Therapeutic Effect; Time; Translating; Treatment Efficacy; Up-Regulation; Work; age related; aged; aging population; base; 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; injury stressor; knock-down; macrophage; male; morphometry; mortality; neuron loss; novel; overexpression; oxidative damage; protective effect; pup; receptor; receptor expression; repaired; response; restoration; 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）是最具破坏性的中风亚型，死亡率高， 严重的疾病和残疾。脑出血导致脑损伤的机制是多方面的 也不太了解目前尚无FDA批准的ICH治疗方法。 最近的研究和我们的初步工作表明，星形胶质细胞，细胞已知有一个独特的密集网络， 线粒体（Mt）分泌完整的Mt，在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伤效应时，可防止损伤并促进恢复功能。 虽然MT转移的生物学被认为是稳态的，但其有益作用背后的机制尚不清楚。 Mt的独特功能之一是从其自身的基因组中产生一种小而有效的生物活性分泌肽， 人蛋白（HN;编码于Mt DNA 16 S核糖体RNA区域），通过特异性表面受体发挥作用 存在于大脑中，包括神经元和小胶质细胞上。HN与MT相关的寿命有关， 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 疾病及其临床意义尚不清楚。 我们广泛的初步结果表明：（1）MT从星形胶质细胞向神经元或小胶质细胞的转移是稳定的 并且该转移赋予神经元中的细胞保护和小胶质细胞中的“愈合”表型， 条件(2)小鼠中ICH介导的损伤导致ICH影响的半球中HN的严重损失， 用重组HN（rHN）治疗显著减少了由ICH产生的神经功能缺损。(3)HN或 星形胶质细胞MT转移到神经元导致（a）STAT 3/MnSOD上调和氧化损伤的减少 （B）小胶质细胞中的PPAR γ上调和“愈合”表型，包括增加的吞噬细胞 容量 因此，我们假设Mt衍生的HN，在完整的Mt分泌的内部释放或转移， 星形胶质细胞（或作为重组HN，rHN注射）可以通过增加神经元的数量来减少ICH介导的损伤（1）。 抗氧化损伤（通过上调MT抗氧化Mn-SOD）和支持神经 可塑性;和（2）通过确保“愈合”（吞噬/抗氧化/抗炎/营养）表型， 小胶质细胞，通过转录因子PPAR γ。 我们的具体目标是：（1）建立星形胶质细胞HN和Mt转移的细胞机制 (A)减弱对神经元的损伤，和（B）在一定条件下促进小胶质细胞的“愈合”表型 模拟ICH。(2)确定（体内）Mt/HN介导的翻译值和机制 保护免受ICH造成的损害。(3)确定Mt转移和HN的年龄/性别相关差异 用老年雄性和雌性小鼠观察HN的表达，以及HN对脑出血的治疗作用。