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: 8629805
• 负责人: Halina Offner
• 金额: $ 46.77万
• 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/8629805
• 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.

描述（由申请方提供）：很少有卒中实验室研究雌性动物或使用性别特异性的缺血性脑损伤细胞模型。在某种程度上，这是由于历史假设，即细胞/分子损伤和修复机制在雄性与雌性中相同。两性临床前动物数据的持续缺乏为临床试验者在女性和男性中测试新疗法带来了严重的证据缺口。在本申请中，我们测试了一个总体假设，即大脑和外周免疫系统之间缺血后炎症循环的演变受到生物性别的强烈影响，包括性二态免疫细胞亚群和影响炎症细胞脑-脾-脑循环的关键炎症机制局灶性脑缺血后。目标1将测试 假设发展中的脑缺血性损伤与脑微血管和实质炎症一起诱发脾损伤，这是更深刻的，并且在男性与女性中由不同的免疫细胞群（单核细胞与T淋巴细胞）介导。目的2确定是否由于T淋巴细胞中过氧化物酶体增殖物激活受体α（PPAR <$）水平较低，导致女性缺血后脑中T淋巴细胞介导的损伤更大。这些假设预测：（a）虽然脾切除术通过消除脾内培养的免疫细胞而使两性的受损大脑受益，过继转移对局灶性脑缺血敏感的女性与男性T淋巴细胞到脾切除的同性接受者中选择性地增加了MCAO后女性脑损伤，并且（B）女性对T淋巴细胞的脆弱性，介导的损伤部分是由于缺乏保护性的PPAR信号传导机制。目的3将评估单核细胞从脾脏运输到缺血后的脑是否具有性别特异性。假设是：（a）相对于雌性，雄性表现出更早和更强的CD 45 highCD 11 B+巨噬细胞和CD 11 c+树突状细胞向缺血后脑的募集;（B）这种募集部分是由于雄性单核细胞中较高的基质金属蛋白酶（MMP）-9表达，从而促进其迁移;（c）在局部脑缺血后，CD 11b+（巨噬细胞“敲除”）或CD 11 c+骨髓细胞（树突细胞“敲除”）缺陷的雄性小鼠将比雌性小鼠更大地受益于这些细胞的损失。因此，这项应用的发现可能会导致开发新的中风治疗方法，如用于女性的PPAR？激动剂和用于男性的MMP-9拮抗剂。