权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Cell-specific changes of laminin expression in the CNS in Alzheimer’s disease

阿尔茨海默病中枢神经系统层粘连蛋白表达的细胞特异性变化

基本信息

批准号：
10283460
负责人：
Yao Yao
金额：
$ 41.11万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10283460
关键词：
Address Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Amyloid beta-Protein Antibodies Area Astrocytes Basement membrane Blood - brain barrier anatomy Brain Brain region CRISPR/Cas technology Cells Communities Corpus striatum structure Correlation Studies Dementia Deposition Endothelial Cells Endothelium Event Extracellular Matrix Proteins Genetic Genetic Recombination Hematopoietic Hippocampus (Brain)Immunohistochemistry Individual Knock-in Mouse Knockout Mice Knowledge Label Laminin Leukocytes Maintenance Memory impairment Microglia Modeling Mus Neurodegenerative Disorders Neurons Oligodendroglia Pathogenesis Pathologic Pathology Pericytes Physiological Play Prognosis Protein Isoforms Reporter Research Research Personnel Role Series Severity of illness Source Techniques base blood-brain barrier disruption cell type conditional knockout disorder control in vivo imaging innovation normal aging success tau Proteins tool

项目摘要

Project Summary/Abstract The long-term objectives of this application are to: (1) determine how each individual cell type-derived laminin changes in the basement membrane (BM) under both physiological and pathological conditions, and (2) correlate these laminin alterations with AD pathology to screen for unique laminin changes that are useful in early AD diagnosis (before the onset of dementia or Aβ/tau pathology) and prognosis prediction. This proposal aims to generate an innovative laminin knock-in mouse line that enables accurate assessment of laminin expression in a cell-specific and Cre-dependent manner; and determine the temporary and spatial expression profile of each individual cell type-derived laminin in the BM in normal and AD brains. We have successfully generated the Laminin-mCherry/eGFP knock-in mouse line using CRISPR-Cas9 technique and further validated these mice in the presence and absence of Cre recombination. In Aim 1, we will cross these laminin knock-in mice with various Cre lines to generate a series of cell-specific laminin reporter (Lam-Rep) mice. Using these Lam-Rep mice, we will determine the cellular source of laminin in brain BM, estimate their relative abundance, and characterize the temporary and spatial expression profile of each individual cell type-derived laminin during normal aging. In Aim 2, cell-specific Lam-Rep mice will be crossed into the 5xFAD background. The temporary and spatial expression profile of each individual cell-derived laminin in the resulting Lam-Rep-5xFAD mice and their non-AD Lam-Rep littermates will be determined similarly as described in Aim 1. Successful completion of this study will fill the gap of knowledge in the field by elucidating the cellular source of laminin in brain BM and characterizing the temporary/spatial expression profile of each individual cell type-derived laminin under both normal and AD conditions. These findings will enable correlation studies between loss of specific cell type-derived laminin and AD pathology; and may identify unique laminin changes that are useful in early AD diagnosis and prognosis prediction. In addition, this proposal will also address a critical barrier to progress in the field by generated an innovative laminin knock-in mouse line, which allows labeling of laminin in a cell-specific and Cre- dependent manner. This genetic tool is also valuable to researchers in other fields (e.g. in vivo imaging and leukocyte transmigration). These studies will lead to a breakthrough in laminin/BM research and substantially move the field forward.

项目总结/文摘