Potential of tissue kallikreins as therapeutic targets for neuropsychiatric lupus

组织激肽释放酶作为神经精神狼疮治疗靶点的潜力

• 批准号: 10667764
• 负责人: Uma Sriram
• 金额: $ 23.78万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10667764
• 关键词: Address; Age; Alzheimer' s Disease; Angiotensin-Converting Enzyme Inhibitors; Anxiety; Applications Grants; Astrocytes; Attenuated; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Behavior; Behavioral; Biological Markers; Blocking Antibodies; Blood; Blood - brain barrier anatomy; Blood specimen; Bradykinin; Brain; Captopril; Central Nervous System; Chronic; Clinic; Clinical; Clinical Trials; Coagulation Process; Complex; Congenic Mice; Data; Dendritic Cells; Development; Diagnosis; Disease; Disease Outcome; Failure; Family; Funding; Gene Expression; Genes; Goals; Human; IFNAR1 gene; Immunologics; Impaired cognition; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interferon alpha; Interferons; Ischemia; Kallikrein-Kinin System; Kidney; Kininogenase; Kininogens; Lupus; Lupus Nephritis; Malignant Neoplasms; Mental Depression; Microglia; Modeling; Multiple Sclerosis; Mus; Neuropsychiatric Systemic Lupus Erythematosus; Onset of illness; Oral Administration; Outcome; Outcome Study; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Peripheral; Peripheral Blood Mononuclear Cell; Plasma; Pre-Clinical Model; Process; Production; Psychoses; Publications; Regulation; Renin-Angiotensin System; Research; Role; SLEB1 gene; Serine Protease; Spleen; Study models; Susceptibility Gene; Symptoms; Systemic Lupus Erythematosus; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Time; Tissue Kallikrein; Tissues; Virus Diseases; angiogenesis; anxiety-like behavior; attenuation; blood pressure control; blood-brain barrier crossing; brain cell; depressive symptoms; disease heterogeneity; experimental study; immunoregulation; improved; lupus prone mice; mouse model; nervous system disorder; neuroinflammation; neuropsychiatric symptom; receptor; response; therapeutic candidate; therapeutic target

Title: Potential of tissue kallikreins as therapeutic targets for neuropsychiatric lupus Project summary: Neuropsychiatric lupus (NPSLE) is one of the most common manifestations of human SLE. Symptoms in NPSLE include anxiety, depression and cognitive impairment that present within one year of lupus diagnosis. IFN  (a Type I IFN), used as a therapeutic in certain diseases, causes development of depressive symptoms. We have shown that the kallikrein-kinin system (KKS) [comprised of kallikreins (klks), bradykinins (BKs)] and angiotensin converting enzyme inhibitors (ACEi’s), suppressed Type I IFN responses in murine dendritic cells (DCs) from normal and lupus-prone mice and human peripheral blood mononuclear cells (PBMC). This phenomenon has immense importance, as IFN is a central player in lupus pathogenesis. The KKS not only regulates many classic processes, such as coagulation, angiogenesis, and control of blood pressure, but also inflammation and regulation of brain functions. ACE degrades BK to inactive peptides, while ACEi’s help to restore BK levels, that in turn suppress IFN responses. Klks breakdown kininogens to BKs, increasing BK levels. Using the well- established MRL/lpr and NZBW/F1 lupus-prone mouse models, we showed that short-term oral administration of captopril [a blood-brain barrier- (BBB) crossing, centrally acting CA-ACEi] decreased IFN responsive genes (IRGs) in brain, spleen and kidney, decreased neuroinflammation, and improved depressive-like and anxiety-like behavior. Interestingly, administration of klk1 (a widely expressed tissue klk) in MRL/lpr mice also improved depressive-like behavior, suppressed IRGs, decreased splenic plasmacytoid DCs, and reduced plasma IFN levels. Other studies have shown that klk genes are decreased in lupus patients; giving exogenous klk1 ameliorated kidney pathology in mice. Together, these findings suggest that KKS molecules may be used to control IFN production/responses and other inflammatory responses in SLE and NPSLE. The proposal aims are to investigate: (1) effects of klk1 on systemic and NPSLE disease outcomes (clinical, pathological, immunological and behavioral) in the spontaneous MRL/lpr mouse model (2) the immunomodulatory effects of klk1 in brain cells of lupus prone (MRL/lpr and Sle 1,2,3) and wild type (MRL/wt, B6) mice. Findings from this proposal will provide a rationale for therapeutic use of klk molecules for systemic lupus and NPSLE.

标题：组织Kallikreins作为神经精神狼疮的治疗靶标的潜力 项目摘要： 神经精神狼疮（NPSLE）是人SLE最常见的表现之一。 NPSLE的症状 包括动画，抑郁和认知障碍，这些障碍会在狼疮诊断的一年内出现。 ifn（a 在某些疾病中用作治疗性的I型IFN）会导致抑郁症状的发展。我们有 表明Kallikrein-Kinin系统（KKS）[由Kallikreins（KLKS），Bradykinins（BKS）和血管紧张素组成 转换酶抑制剂（ACEI），抑制了鼠树突状细胞中的I型IFN反应（DC） 正常和狼疮的小鼠以及人类外周血单核细胞（PBMC）。这种现象有 巨大的重要性，因为IFN是狼疮发病机理的中心参与者。 KKS不仅规范了许多经典 过程，例如凝血，血管生成和血压的控制，以及炎症和 调节大脑功能。 Ace将BK降低到无活跃的辣椒，而ACEI有助于恢复BK水平，这是 反过来抑制IFN响应。 KLKS分解运动成胶对BKS，增加了BK水平。使用井 已建立的MRL/LPR和NZBW/F1狼疮的小鼠模型，我们表明了短期给药 卡托普利[血脑屏障（BBB）横断，中央作用CA-ACEI]的降低IFN反应性基因 （IRGS）在大脑，sleen和肾脏中，改善神经炎症，并改善类似抑郁症和动画状 行为。有趣的是，MRL/LPR小鼠中的KLK1（广泛表达的组织KLK）也有所改善 抑郁样的行为，抑制IRG，脾血浆todoid dcs降低，血浆IFN血浆降低 水平。其他研究表明，狼疮患者的KLK基因降低。给出外源性KLK1 小鼠改善肾脏病理学。这些发现一起表明KKS分子可以用来 控制SLE和NPSLE中的IFN产生/反应以及其他炎症反应。提案 目的是研究：（1）KLK1对系统性和NPSLE疾病结果的影响（临床，病理，病理， 在赞助MRL/LPR小鼠模型中的免疫学和行为）（2）免疫调节作用 狼疮俯卧（MRL/LPR和SLE 1,2,3）和野生型（MRL/WT，B6）小鼠的脑细胞中的KLK1。从中的发现 提案将为全身性狼疮和NPSLE提供治疗用途的治疗用途提供理由。