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

基本信息

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
项目类别：
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&apos 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

项目摘要

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：组织激肽释放酶作为神经精神狼疮治疗靶点的潜力项目概要：神经精神狼疮 (NPSLE) 是人类 SLE 最常见的症状之一。包括狼疮诊断后一年内出现的焦虑、抑郁和认知障碍。 I 型干扰素）用作某些疾病的治疗剂，会导致抑郁症状的发生。显示激肽释放酶-激肽系统 (KKS) [由激肽释放酶 (KLKS)、缓激肽 (BKs) 组成] 和血管紧张素转化酶抑制剂 (ACEi) 可抑制小鼠树突状细胞 (DC) 中的 I 型 IFN 反应正常和易患狼疮的小鼠和人外周血单核细胞（PBMC）都有这种现象。非常重要，因为 IFNα 是狼疮发病机制的核心参与者，KKS 不仅调节许多经典的功能。过程，例如凝血、血管生成和血压控制，还有炎症和 ACE 可以调节大脑功能，将 BK 降解为非活性肽，而 ACEi 则有助于恢复 BK 水平。反过来抑制 IFN 反应，将激肽原分解为 BK，从而提高 BK 水平。建立了 MRL/lpr 和 NZBW/F1 狼疮易感小鼠模型，我们表明短期口服给药卡托普利 [血脑屏障 - (BBB) 穿越，中枢作用 CA-ACEi] 减少 IFN 反应基因（IRG）在大脑、脾脏和肾脏中，减少神经炎症，改善抑郁样和焦虑样隐含地，对 MRL/lpr 小鼠施用 klk1（一种广泛表达的组织 klk）也有所改善。抑郁样行为、IRG 抑制、脾浆细胞样 DC 减少和血浆 IFNα 减少其他研究表明，给予外源性 klk1 后，狼疮患者的 klk 基因水平会降低。总之，这些发现表明 KKS 分子可用于改善小鼠的肾脏病理。控制 SLE 和 NPSLE 中的 IFNα 产生/反应和其他炎症反应。目的是研究：(1) klk1 对全身性和 NPSLE 疾病结果（临床、病理、自发 MRL/lpr 小鼠模型中的免疫学和行为学）（2）免疫调节作用狼疮易感小鼠（MRL/lpr 和 Sle 1,2,3）和野生型（MRL/wt，B6）小鼠脑细胞中的 klk1。该提案将为 klk 分子治疗系统性狼疮和 NPSLE 提供依据。