Humanin and Intracerebral Hemorrhage

护脑素与脑出血

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

抽象的脑出血（ICH）是最具破坏性的中风亚型，死亡率很高， ICH 导致脑损伤的机制是多方面的。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（已知具有独特致密网络的细胞）线粒体 (Mt) 分泌完整的 Mt，进入邻近的神经元或小胶质细胞后可以帮助它们抵抗当暴露于脑内血液制品的损伤作用时，可以减轻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基因组中产生一种小而有效的生物活性分泌肽，护脑素（HN；编码于 Mt DNA 16S 核糖体 RNA 区域），通过特定的表面受体发挥作用 HN 存在于大脑中，包括神经元和小胶质细胞，与 Mt 相关的长寿有关。然而，HN 对脑血管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) 从星形胶质细胞到神经元或小胶质细胞的稳健 Mt 转移并且这种转移赋予神经元细胞保护作用，并在 ICH 样条件下赋予小胶质细胞“愈合”表型 (2) ICH 介导的小鼠损伤导致受 ICH 影响的半球 HN 严重丧失。重组 HN (rHN) 治疗可显着减少 ICH (3) HN 或造成的神经功能缺损。星形胶质细胞 Mt 转移至神经元导致 (a) STAT3/MnSOD 上调并减少氧化损伤 (b) 小胶质细胞中 PPAR 上调和“治愈”表型，包括吞噬细胞增加容量。因此，我们认为 Mt 衍生的 HN 在完整的 Mt 中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减少 ICH 介导的损伤 (1) 抵抗氧化损伤（通过上调 Mt 抗氧化 Mn-SOD）并支持神经可塑性；（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。我们的具体目标是： (1) 建立（体外）星形胶质细胞 HN 和 Mt 转移的细胞机制 (A) 减轻对神经元的损伤，(B) 在一定条件下促进小胶质细胞的“愈合”表型 (2) 确定（体内）Mt/HN 介导的翻译价值和机制。保护免受 ICH 造成的损害 (3) 确定 Mt 转移和 HN 中与年龄/性别相关的差异。使用老年雄性和雌性小鼠进行表达，以及 HN 在 ICH 中的治疗效果。