A system approach to targeting innate immunity in AD

针对 AD 先天免疫的系统方法

基本信息

批准号：
9349746
负责人：
NILUFER ERTEKIN-TANER
金额：
$ 15.65万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-20 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9349746
关键词：
Age-associated memory impairment Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Behavior Biological Biological Response Modifiers Brain Code Cognition Complement Data Deposition Development Disease Gene Chips Gene Delivery Gene Expression Genes Genetic Gliosis Goals Health Human Immune Immune Targeting Immune system Immunotherapy Institution Intervention Intervention Studies Knowledge Liquid substance Medical Mining Modeling Modification Monitor Mus Mutation Natural Immunity Nerve Degeneration Pathology Pathway interactions Phagocytosis Phenotype Play Proteins Recombinants Research Infrastructure Role Sampling Signal Pathway Signal Transduction Signaling Protein Staging System Tauopathies Technology Therapeutic Time Tissues Transgenic Mice Validation Variant Virus aging brain base cognitive function comparative complement system effective therapy extracellular genetic association genetic risk factor immune activation in vivo innate immune function insight mouse model new therapeutic target novel novel therapeutics pathological aging pre-clinical prophylactic protein aggregate research study response risk variant targeted treatment tau Proteins therapeutic target transcriptome sequencing transcriptomics validation studies

Age-associated memory impairment Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Behavior Biological Biological Response Modifiers Brain Code Cognition Complement Data Deposition Development Disease Gene Chips Gene Delivery Gene Expression Genes Genetic Gliosis Goals Health Human Immune Immune Targeting Immune system Immunotherapy Institution Intervention Intervention Studies Knowledge Liquid substance Medical Mining Modeling Modification Monitor Mus Mutation Natural Immunity Nerve Degeneration Pathology Pathway interactions Phagocytosis Phenotype Play Proteins Recombinants Research Infrastructure Role Sampling Signal Pathway Signal Transduction Signaling Protein Staging System Tauopathies Technology Therapeutic Time Tissues Transgenic Mice Validation Variant Virus aging brain base cognitive function comparative complement system effective therapy extracellular genetic association genetic risk factor immune activation in vivo innate immune function insight mouse model new therapeutic target novel novel therapeutics pathological aging pre-clinical prophylactic protein aggregate research study response risk variant targeted treatment tau Proteins therapeutic target transcriptome sequencing transcriptomics validation studies

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项目摘要

DESCRIPTION (provided by applicant): An invariant feature of the pathological cascade in Alzheimer's diseases (AD) is a reactive gliosis, reflecting an underlying alteration in the innate immune activation state within the brain. Innate immune signaling is altered early in AD, but is also skewed towards an activated state as a consequence of brain aging. There is strong genetic evidence that innate immunity has a significant role in AD. Variants in two genetic loci that play roles in the complement cascade, CR1 and CLU, show significant genetic associations with AD, and rare coding variants in TREM2 also confer substantial risk for AD. Numerous experimental studies in AD mouse models show that manipulating innate immune pathways can have positive or negative effects on proteostasis, cognition and neurodegeneration. At least when assessing A� pathology as an endpoint, the beneficial effects of some innate immune system manipulations are robust. We propose to identify therapeutic targets within the innate immune signaling cascade in AD that could be safely manipulated to provide disease modification in AD. However, because of the complexity of, and the gaps in our knowledge regarding, innate immune signaling within the CNS, a systems level approach that integrates multiple types of data will be required to achieve this goal. Indeed, development of any innate immune therapy will need to be finely tuned and extensively validated in order to be further developed as a potential AD therapy. We will use a multifaceted systems level approach to identify targets within innate immune signaling pathways that can safely provide disease modifying effects in AD. Comprehensive, transcriptomic, genetic and pathological data from both humans and mouse models will be generated, integrated and analyzed in novel ways. This integrated data will then be used to guide multiple preclinical target validation studies of key innate immune targets in both APP and tau mouse models as well as non-transgenic mice. These studies will dramatically accelerate the identification and validation of disease modifying innate immune modulatory strategies in AD and will provide important insights into how these various manipulations of innate immune activation states alter normal behaviors with an emphasis on cognition.