Sex differences in brain inflammation in experimental stroke

实验性脑卒中脑部炎症的性别差异

• 批准号: 8293940
• 负责人: Stephanie J Murphy
• 金额: $ 49.36万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8293940
• 关键词: Adoptive Transfer; Affect; Agonist; Animals; Apoptosis; Astrocytes; Autoimmune Diseases; Biological; Biological Preservation; Blood; Blood - brain barrier anatomy; Brain; Brain Injuries; Brain Ischemia; Cause of Death; Cell Death; Cell model; Cells; Cerebral Ischemia; Cerebrum; Cessation of life; Clinical; Clinical Research; Dendritic Cells; Development; Encephalitis; Event; Evolution; Exhibits; Female; Gelatinase B; Glutathione; Human; ITGAM gene; ITGAX gene; Immune; Immune response; Immune system; Immunosuppression; Infarction; Inflammation; Inflammatory; Injury; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Knock-out; Laboratory Study; Lead; Mediating; Molecular; Multiple Sclerosis; Mus; Myeloid Cells; New Territories; Nitric Oxide Synthase; Outcome; PPAR alpha; Pathology; Pathway interactions; Patients; Peripheral; Peroxisome Proliferator-Activated Receptors; Phenotype; Poly(ADP-ribose) Polymerases; Population; Predisposition; Process; Recovery; Relative (related person); Risk; Sex Characteristics; Shapes; Signal Transduction; Spleen; Splenectomy; Stroke; Survivors; T-Lymphocyte; Testing; Time; United States; Woman; Work; animal data; apoptosis inducing factor; caspase-3; central nervous system injury; disability; immune depression; injured; injury and repair; innovation; killings; macrophage; male; men; monocyte; novel; post stroke; pre-clinical; research study; sex; stroke therapy; trafficking

DESCRIPTION (provided by applicant): Few stroke laboratories study female animals or use cell models of ischemic brain injury that are sex-specific. In part, this is due to the historical assumption that cellular/molecular injury and repair mechanisms are the same in males vs. females. The persistent lack of pre-clinical animal data in both sexes poses a severe evidence gap for clinical trialists who will test new therapies in women and men. In this application, we test the overarching hypothesis that the evolution of post-ischemic inflammatory cycling between the brain and peripheral immune system is strongly influenced by biological sex, including sexually dimorphic immune cell subsets and key inflammatory mechanisms that affect brain-spleen-brain cycling of inflammatory cells after focal cerebral ischemia. Aim 1 will test the hypotheses that evolving cerebral ischemic injury elicits splenic damage in tandem with brain microvascular and parenchymal inflammation that is more profound and is mediated by different immunocyte populations (monocytes vs. T lymphocytes) in males vs. females. Aim 2 determines if T lymphocyte-mediated injury in post-ischemic brain is greater in females due to lower levels of peroxisome proliferator activated receptor alpha (PPAR¿) in T lymphocytes. These hypotheses predict that (a) while splenectomy benefits the injured brain of both sexes by eliminating immunocytes nurtured within the spleen, adoptive transfer of female vs. male T lymphocytes sensitized to focal cerebral ischemia into splenectomized same sex recipients selectively increases female cerebral damage more so than males following MCAO and that (b) female vulnerability to T lymphocyte-mediated injury is due in part to a lack of protective PPAR¿ signaling mechanisms. Aim 3 will evaluate whether monocyte trafficking from spleen to post- ischemic brain is sex-specific. The hypotheses are that (a) males exhibit an early and more robust recruitment of CD45highCD11b+ macrophages and CD11c+ dendritic cells into post-ischemic brain relative to females; (b) this recruitment is due in part to higher matrix metalloproteinase (MMP)-9 expression in male monocytes, thus facilitating their transmigration; (c) male mice deficient in CD11b+ (macrophage "knockout") or in CD11c+ myeloid cells (dendritic cell "knockout") will more greatly benefit by loss of these cells than will females following focal cerebral ischemia. Findings from this application could therefore lead to the development of new therapies for stroke such as PPAR¿ agonists for females and MMP-9 antagonists for males. PUBLIC HEALTH RELEVANCE: Ischemic stroke is a leading cause of death and disability in the United States, yet relatively little is known about the contribution to and effects on the immune system during stroke. The application focuses on early and late events in the peripheral immune system during stroke and important changes in the spleen that occur simultaneously with the evolving brain injury. We have preliminary evidence that this process is not identical in both males and females and are studying the relevant sex differences.

描述（由适用提供）：很少有卒中实验室研究雌性动物或使用特定性别的缺血性脑损伤的细胞模型。在某种程度上，这是由于历史假设，即男性与女性的细胞/分子损伤和修复机制相同。两性中缺乏临床前动物数据的持续缺乏为临床试验者带来了严重的证据差距，这些临床试验者将测试男女的新疗法。在此应用中，我们检验了以下总体假设：大脑和周围免疫系统之间缺血后炎症循环的演变受生物性别的强烈影响，包括影响脑部脑浆液后炎性细胞的性脑膜脑循环的性二态性免疫细胞亚群和关键炎症机制。 AIM 1将测试 假设在脑缺血性损伤中随着脑微血管和副型感染引起脾脏损伤，这些损伤更深刻，并且是由不同的免疫细胞群体（单核细胞与T. T淋巴细胞）与男性相比于男性的介导的。 Aim 2 determines if T lymphocyte-mediated injury in post-ischemic brain is greater in females due to lower levels of peroxysome proliferator activated receptor alpha (PPAR¿) in T These hypotheses predict that (a) while splenectomy benefits the injured brain of both sexes by eliminating immunocytes nursed within the spleen, adaptive transfer of female vs. male T lymphocytes sensitive to与MCAO后的男性相比，局灶性脑缺血与脾脏相同的性接受者有选择地增加女性脑损伤，并且（b）女性对T淋巴细胞介导的损伤的脆弱性部分是由于缺乏保护性PPAR损害信号机制。 AIM 3将评估单核细胞从Sleen到缺血后大脑是否具有性别特异性。假设是（a）雄性对CD45-HighCD11b+巨噬细胞和CD11C+树突状细胞的早期且更强大的募集相对于女性而言相对于雌性而言。 （b）这种募集的部分原因是雄性单核细胞中较高的基质金属蛋白酶（MMP）-9表达，因此支持其传播； （c）雄性小鼠缺乏CD11b+（巨噬细胞“基因敲除”）或CD11C+髓样细胞（树突状细胞“敲除”），这些细胞的损失比局灶性脑缺血后会更大的好处。因此，该应用的结果可能导致开发中风的新疗法，例如女性的PPAR pPARMANISTS和男性MMP-9拮抗剂。 公共卫生相关性：缺血性中风是美国死亡和残疾的主要原因，但对中风期间对免疫系统的贡献和影响相对较少。该应用的重点是中风期间外周种免疫系统的早期和晚期事件，并且脾脏的重要变化只是随着不断发展的脑损伤而发生的。我们有初步的证据表明，在男性和女性中，这一过程都不相同，并且正在研究相关的性别差异。