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Control of extracellular matrix remodeling by CD29+ astrocytes

CD29 星形胶质细胞对细胞外基质重塑的控制

基本信息

批准号：
10494593
负责人：
Michael Alex Wheeler
金额：
$ 38.47万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10494593
关键词：
Acute Affect Animals Astrocytes Automobile Driving Bar Codes Behavior Behavioral Paradigm Binding Blood - brain barrier anatomy Cell Communication Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Chronic Chronic stress Complex Corpus striatum structure Data Deposition Disease Environment Environmental Risk Factor Exhibits Exposure to Extracellular Matrix Extracellular Matrix Proteins Family Goals Heterogeneity Image Inflammation Integrin alpha Chains Integrin beta Chains Integrins Interneurons Italy Lead Ligands Location Maps Measures Membrane Proteins Mental Health Methods Molecular Mus Neuraxis Neuroglia Neurons Nucleus Accumbens Operant Conditioning Parvalbumins Peptides Play Population Process Proteoglycan Publishing RNA Regulation Research Rewards Role Shapes Specific qualifier value Stress Structure Surface Techniques Testing Tracer Viral acute stress base behavior influence behavioral response cell type genome-wide high throughput screening in vivo in vivo calcium imaging multiple omics neuroregulation novel receptor relating to nervous system response single-cell RNA sequencing stressor tool transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT Remodeling of the extracellular matrix (ECM) is a central mechanism by which central nervous system (CNS) reward substrates, such as the nucleus accumbens (NAc), adapt to unpredictable stressors in the environment. The ECM is a spatially, molecularly, and cellularly heterogeneous structure that impacts neural activity, cell-cell interactions, and blood-brain barrier integrity. However, exposure to repeated unpredictable stress leads to molecular and cellular reorganization of the ECM, which influences circuit-level adaptations to stress guiding neural activity and behavior. ECM remodeling is partially controlled by integrins: transmembrane receptors that regulate the ECM by anchoring ECM-associated peptides to multiple cell types. Cellularly, the ECM consists of neuronal processes and also the endfeet of astrocytes, which are CNS-resident glial cells. Astrocytes make contacts throughout the ECM by expressing multiple integrins that actively participate in ECM remodeling. Through these intimate interactions within the ECM, astrocytes are poised to control neural activity and behavior. However, the mechanisms and cell-cell interactions by which astrocytes shape the NAc ECM in response to unpredictable stress are largely unknown. In PREVIOUS RESEARCH EFFORTS I focused on characterizing the responses of astrocyte subsets in the CNS in response to inflammation. I identified the b1 integrin CD29 as a top marker expressed by astrocytes throughout the CNS. CD29 participates in multiple complexes with other integrins that affect ECM organization. My previous data suggest that CD29+ astrocytes might be composed of heterogeneous subsets that play complementary roles in remodeling the ECM by interacting with distinct cell types. However, it has been historically challenging to rapidly study the interactions of astrocyte subsets in vivo. To this end, I recently developed a new technique called RABID-seq that profiles astrocyte interactions with other cells at high throughput, on the genome-wide scale, and with single-cell transcriptomic precision. Thus, RABID- seq is a candidate tool to define the interactions of CD29+ astrocyte subsets in the ECM in response to unpredictable stress. In this proposal, I AM PURSUING A NEW RESEARCH DIRECTION to identify how exposure to unpredictable stress shapes CD29+ astrocyte interactions, localization, and function. I hypothesize that defined subsets of CD29+ astrocytes regulate distinct ECM domains that influence behavioral responses to unpredictable stress. I propose to test this hypothesis in the following Specific Aims. In Aim 1, I will define the interactions of integrin-expressing CD29+ astrocyte subsets within the NAc in response to acute and chronic unpredictable stress using RABID-seq and CITE-seq. In Aim 2, I will spatially map the ECM domains occupied by each subset of CD29+ NAc astrocytes via spatial transcriptomics and CD29 cKO mice to uncover how CD29+ astrocytes remodel the ECM in response to stress. In Aim 3, I will define how CD29+ NAc astrocytes regulate the activity of parvalbumin+ interneurons in a reward-seeking paradigm after exposure to unpredictable stress. IN SUMMARY, I will study how stress affects the interactions, location, and function of NAc CD29+ astrocytes.

项目总结/文摘