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; 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.

抽象的 脑内出血（ICH）是中风的最毁灭性亚型，死亡率高，并且 深刻的发病率和残疾。导致由ICH造成的脑损伤的机制是多方面的 并且理解很差。 ICH没有FDA批准的治疗方法。 最近的研究和我们的初步工作表明，星形胶质细胞，已知具有独特密度网络的细胞 线粒体（MT），秘密完整MT，进入相邻神经元或小胶质细胞时可以帮助它们抵抗 当暴露于脑血液产物的损伤影响时，受伤并促进恢复功能。 尽管MT转移的生物学被视为体内平衡，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其自身的基因组中产生一个小潜在的生物活性秘书胡椒， Humanin（HN；在MT DNA 16S核糖体RNA区域编码），该区域通过特定的表面受体作用 存在于大脑中，包括神经元和小胶质细胞。 HN与MT相关的长寿与 细胞保护活动。但是，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尚不清楚。 我们广泛的初步结果证明：（1）从星形胶质细胞到神经元或小胶质细胞的强大MT转移 并且转移承认神经元中的细胞技术和在类似ICH的小胶质细胞中的“愈合”表型 状况。 （2）小鼠ICH介导的损伤导致ICH影响的半球的HN损失严重损失 重组HN（RHN）的治疗显着降低了ICH产生的神经系统缺陷。 （3）HN或 星形细胞MT转移到神经元中导致（a）STAT3/MNSOD上调和减少氧化损伤 对神经元和（b）小胶质细胞和“愈合”表型的PPAR上调，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中释放或转移 星形胶质细胞（或注射为重组HN，RHN）可以通过增加神经元来减少ICH介导的损伤（1） 抵抗氧化物损伤（通过上调MT抗氧化Mn-SOD），并通过支持中性 可塑性; （2）通过确保“治愈”（吞噬/抗氧化/抗炎/营养）表型 小胶质细胞，通过转录因子PPAR。 我们的具体目的是：（1）（1）（体外）星形细胞HN和MT转移的细胞机制 （a）减弱对神经元的损伤，（b）在条件下促进小胶质细胞的“愈合”表型 模拟ICH。 （2）确定（体内）MT/HN培养的翻译价值和机制 防止ICH施加的损害。 （3）在MT转移中建立与年龄/性别有关的差异 使用老年男性和雌性小鼠的表达，以及ICH中HN的治疗作用。