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.

组织激肽释放酶作为神经精神性狼疮治疗靶点的潜力 项目概要： 神经精神性狼疮（NPSLE）是人类SLE最常见的表现之一。NPSLE的症状 包括在狼疮诊断后一年内出现焦虑、抑郁和认知障碍。干扰素α I型干扰素），用作某些疾病的治疗，导致抑郁症状的发展。我们有 表明激肽释放酶-激肽系统（KKS）[由激肽释放酶（klks）、缓激肽（BK）组成]和血管紧张素 转化酶抑制剂（ACEi），抑制小鼠树突状细胞（DC）中的I型IFN应答， 正常和狼疮易感小鼠和人外周血单核细胞（PBMC）。这一现象 非常重要，因为IFN γ是狼疮发病机制中的核心参与者。KKS不仅规范了许多经典的 过程，如凝血、血管生成和血压控制，而且还有炎症和 调节大脑功能。ACE将BK降解为无活性肽，而ACEi有助于恢复BK水平， 继而抑制IFN应答。Klks将激肽原分解为BK，增加BK水平。利用这口井- 建立MRL/lpr和NZBW/F1狼疮易感小鼠模型， 巯甲丙脯酸[血脑屏障-（BBB）交叉，中枢作用CA-ACEi]减少IFN应答基因 （IRGs），减少神经炎症，改善抑郁样和焦虑样 行为有趣的是，在MRL/lpr小鼠中给予klk 1（一种广泛表达的组织klk）也改善了 抑郁样行为、IRG抑制、脾浆细胞样DC减少和血浆IFN γ减少 程度.其他研究表明，klk基因在狼疮患者中减少，给予外源性klk 1 改善小鼠的肾脏病理学。总之，这些发现表明，KKS分子可以用于 在SLE和NPSLE中控制IFN γ的产生/反应和其他炎症反应。该提案 目的是研究：（1）klk 1对全身和NPSLE疾病结果（临床，病理， 免疫学和行为学）在自发MRL/lpr小鼠模型中的作用（2） klk 1在狼疮倾向（MRL/lpr和Sle 1、2、3）和野生型（MRL/wt，B6）小鼠的脑细胞中的表达。时发现的问题 该提案将为klk分子用于系统性狼疮和NPSLE的治疗用途提供理论基础。