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INVESTIGATION OF COMPLEMENT INDUCED NEUROTOXIC AND NEUROPROTECTIVE PATHWAYS

补体诱导的神经毒性和神经保护途径的研究

基本信息

批准号：
7347989
负责人：
Andrea Joan Tenner
金额：
$ 24.23万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-08-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7347989
关键词：
AD transgenic mice Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Anaphylatoxin Anaphylatoxins Anti-Inflammatory Agents Anti-inflammatory Apoptotic Area Binding Biological Assay Brain Brain region Brain-Derived Neurotrophic Factor Bulla C5a anaphylatoxin receptor Cell Death Cells Cessation of life Characteristics Classical Complement Pathway Clinical Cognitive Collaborations Complement Complement 3a Complement 3b Complement 5a Complement Activation Complex Condition Data Deposition Diagnosis Disease Disease Progression Down Syndrome Elderly Elements Equilibrium Event Exposure to Functional disorder Gene Expression Generations Gliosis Goals Hippocampus (Brain)Human Immune response Immune system Impaired cognition In Vitro Individual Infection Infiltration Inflammation Inflammatory Ingestion Injection of therapeutic agent Injury Interleukin-6 Investigation Knockout Mice Lead Left Mediating Microglia Modeling Modification Mus Myeloid Cells Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Outcome Oxidative Stress Pathology Pathway interactions Patients Peptides Performance Peripheral Phagocytosis Phase Play Predisposition Preparation Principal Investigator Process Production Program Research Project Grants Property Reagent Regulation Reporting Research Resistance Rodent Rodent Model Role Senile Plaques Signal Pathway Signal Transduction Solid Staging Stress System Testing Tg2576 Therapeutic Time Tissues Toxic effect Transgenic Organisms Up-Regulation Vascular Dementia activation product amyloid peptide amyloid precursor protein processing base cognitive function complement C5a-inhibitors cytokine design extracellular in vivo inhibitor/antagonist injured insight loss of function macrophage mitochondrial dysfunction mouse model neuroinflammation neuron loss neuroprotection neurotoxic neurotrophic factor normal aging novel particle prevent programs receptor receptor expression repaired research study response response to injury tau Proteins therapeutic target thioflavine

项目摘要

Project 4: Neuroprotection and neuroinflammation induced by the complement proteins Clq and C5a The complement system is a component of the innate immune system whose function is to recognize deviations from the norm (such as an infection or tissue injury) and to initiate a response that will protect and initiate repair of the injured area. If not properly regulated however, tissue damage results. Previous observations suggest a detrimental effect of the activation of the complement cascade at a late stage of Alzheimer's disease when amyloid plaques containing the fibrillar, and thus complement activating, form of the amyloid peptide, AB, accumulate. Clq, the recognition component of one pathway of complement activation, binds to fibrillar amyloid and activates the pathway. One downstream product of complement activation is C5a which is known to enhance inflammation by binding to specific receptors. In this proposal, a C5a receptor antagonist which has proven effective in limiting complement mediated inflammation in other models, is being tested as a potential targeted therapy in AD mouse models. This point of inhibition would leave the remainder of the complement cascade intact, thereby permitting potentially beneficial effects of complement, such as enhanced clearance of abnormal (amyloid) deposits (by C3b), apoptotic cells and/or cellular debris (by Clq and C3b). However, it is also becoming increasingly evident that there are both activating and modulating/decoy receptors for C5a expressed in brain, and thus we propose to determine whether the balance of expression of these receptors dictates the degree of inflammation in the AD brain. In addition, Clq, which is known to be synthesized and secreted as a response to injury, has recently been shown to down regulate proinflammatory cytokines in peripheral macrophages and to provide survival signals to neurons in vitro. Using several in vitro approaches, the basis for these neuroprotective events will be defined. Results of these proposed studies should provide solid data on the significance of the contribution of complement-induced inflammatory events in AD and likely other neurodegenerative disease in the aging individual. Therapeutic inhibitors of detrimental processes identified here as well as reagents or treatments that promote the neuroprotective functions induced can subsequently be designed to slow the progression of this pervasive disease of the elderly.

项目4: