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Aberrant Protein Kinase C Signaling in Alzheimer's Disease

阿尔茨海默病中的异常蛋白激酶 C 信号转导

基本信息

批准号：
10901015
负责人：
Kim Bohemie Dore
金额：
$ 90.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2023-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10901015
关键词：
AMPA Receptors Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease pathology Amyloid Amyloid beta-Protein Automobile Driving Binding Biochemical Biological Markers Biosensor Brain Brain Diseases Brain region Cognition DLG1 gene DLG4 gene Data Dementia Diglycerides Disease Electrophysiology (science)Enzymes Event Family Functional disorder Genes Germ-Line Mutation Goals Homeostasis Image Impaired cognition Impairment Individual Inflammatory Isoenzymes Late Onset Alzheimer Disease Learning Ligands Malignant Neoplasms Measures Mediating Memory Methods Microglia Molecular Mus Mutation N-Methyl-D-Aspartate Receptors Nerve Degeneration Neurons PRKCA gene Pathway Analysis Phosphorylation Play Protein Analysis Protein Kinase Protein Kinase C Proteins Proteomics Public Health Research Role Scaffolding Protein Second Messenger Systems Senile Plaques Signal Pathway Signal Transduction Signaling Protein Site Surface Synapses Synaptic Receptors Synaptic Transmission Testing Therapeutic Variant Vision affection age related brain size cancer clinical trial design disease phenotype extracellular fluorescence lifetime imaging genome editing genome sequencing genome wide association study kinase inhibitor mouse model neuron loss neurotransmission novel therapeutic intervention phosphoproteomics protein function protein kinase C kinase rare variant scaffold segregation synaptic depression synaptic function therapeutic target whole genome

项目摘要

Summary/Abstract The overall vision of our proposed research is to understand the molecular, cellular and electrophysiological mechanisms by which aberrant signaling by protein kinase C (PKC) promotes the pathology of Alzheimer’s Disease (AD). This age-related dementia is characterized by deregulated signaling, degeneration of synapses, neuronal death and, ultimately, a reduction in the size of brain regions involved in learning and memory. While significant efforts have been devoted to understanding the role of extracellular amyloid-β (Aβ) plaques that are a hallmark of the disease, emerging evidence points to deregulated signaling by PKC isozymes playing a potentially causative role in the disease. We have assembled a team with extensive and complementary expertise in PKC mechanisms and synaptic mechanisms to understand how aberrant PKC signaling contributes to the disease phenotype. Recent searches for rare functional variants associated with AD from whole genome sequencing data from families with late-onset AD have identified highly penetrant variants in the genes for both PKC (PRKCA) and PKC (PRKCH) in multiple families that co-segregate with AD affection status. All PKC variants display enhanced activity, and our detailed analysis of one variant (PKC M489V) has established that it is sufficient to rewire the brain phosphoproteome, drive synaptic degeneration, and impair cognition in a mouse model. Enhanced PKC function driving AD pathology is consistent with unbiased phosphoproteomics analysis that have identified elevated PKC signaling as one of the earliest events in AD diseased brains. Thus, the hypothesis driving this proposal is that two PKC isozymes, PKC in neurons and PKC in microglia, play essential roles in brain homeostasis and that deregulation of either contributes to the pathology of AD. We aim to combine state-of-the-art proteomics, biochemical, imaging and electrophysiological approaches in order to study molecular mechanisms of how aberrant signaling by PKC or PKC impact neuronal or microglial function. We also will test the hypothesis that increased protein levels of either PKC is a biomarker in AD. This project should make significant strides in our understanding of neurodegeneration and AD as well as providing possible new therapeutic strategies against this devastating disease.

摘要/文摘