IRAK4 and Systemic Lupus Erythematosus

IRAK4 和系统性红斑狼疮

基本信息

批准号：
10118270
负责人：
Anthony T Vella
金额：
$ 40.96万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10118270
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Amyloid deposition Antibodies Applications Grants Area Attenuated Autoimmune Diseases Award Behavioral Biological Assay Biology Blood Blood - brain barrier anatomy Brain Central Nervous System Diseases Chemicals Clinical Cognition Cognitive Cognitive deficits Cytometry Department chair Development Diagnostic Disease Drug Design Endothelium Exhibits Flow Cytometry Functional disorder Future Grant Health Histologic Human IRAK4 gene Image Immunology Impaired cognition In Situ Inflammation Inflammatory Investigation Link Lupus Manuscripts Mass Spectrum Analysis Measures Memory Memory impairment Mental Depression Methods Modeling Molecular Mus Names Neuraxis Neurobehavioral Manifestations Neurodegenerative Disorders Neuropsychiatric Systemic Lupus Erythematosus Neurosciences Pathway interactions Patients Peripheral Nervous System Phenotype Phosphotransferases Play Population Pristane Process Measure Reporting Research Role Scientist Senile Plaques Serum Signal Pathway Signal Transduction Signaling Molecule Symptoms Syndrome Systemic Lupus Erythematosus Testing Time Toll-like receptors Work aged base behavioral impairment brain cell brain endothelial cell brain tissue cellular targeting chemokine cognitive function cognitive performance cognitive process dementia risk design experimental study in vivo inflammatory marker inhibitor/antagonist innovation lupus-like mouse model neurobehavioral neuroinflammation new therapeutic target novel novel therapeutic intervention professor single cell analysis therapeutic target translational study

项目摘要

Summary Systemic lupus erythematosus (SLE) is a devastating autoimmune disease that affects 5 million people worldwide. Frequently, SLE affects the central and peripheral nervous system, a syndrome collectively named neuropsychiatric SLE (NPSLE). Cognitive dysfunction (CD) is a significant problem in NPSLE that is reported to affect a broad range of patients, reflecting the complexity of the disease, the lack of standard criteria for diagnostics, and the need for additional research. Accumulating evidence demonstrates the involvement of Toll-like receptors (TLRs) in SLE, and IRAK4 is a key kinase that initiates signaling by most TLRs involved in SLE. By studying the role of IRAK4 in SLE prone mice we found a link between lupus and brain microvascular endothelial cells, and importantly, detected specific chemokines that are also associated with CD. We hypothesize that inhibition of IRAK4 activity will alleviate NPSLE by reducing CD. This will be tested by identifying the cellular and molecular brain alterations in a lupus mouse model in which the IRAK4 activity is abolished that include, profiling brain and serum chemokines and also activation states and signaling pathways in brain tissue using cutting-edge Imaging Mass Spectrometry analysis. Lastly, we will test if abolishing IRAK4 activity impacts CD using the same model. These findings will advance our understanding of IRAK4 signaling in NPSLE, facilitate design of drugs to attenuate CD, and pave the way for translational studies in NPSLE patients.

概括全身性红斑狼疮（SLE）是一种毁灭性的自身免疫性疾病，影响500万全球人。 SLE通常会影响中央和周围神经系统，综合征共同命名为神经精神病学SLE（NPSLE）。认知功能障碍（CD）是重要的据报道，NPSLE的问题会影响广泛的患者，反映了疾病，缺乏诊断标准标准以及需要进行其他研究。积累的证据表明，Toll样受体（TLR）参与SLE和 irak4是一种关键的激酶，它启动了大多数参与SLE的TLR的信号传导。通过研究角色 irak4在sle容易发小鼠中，我们发现了狼疮与脑微血管内皮之间的联系细胞，重要的是检测到也与CD相关的特定趋化因子。我们假设抑制IRAK4活性将通过减少CD来减轻NPSLE。这将是通过识别狼疮小鼠模型中的细胞和分子脑的改变来测试消除了IRAK4活性，其中包括大脑和血清趋化因子以及使用尖端成像质量的激活状态和脑组织中的信号通路光谱分析。最后，我们将测试使用相同的IRAK4活动是否会影响CD 模型。这些发现将提高我们对NPSL中IRAK4信号的理解，促进衰减CD的药物设计，为NPSLE患者的翻译研究铺平了道路。