| 2020 — 2021 |
Menon, Vilas |
R01Activity Code Description:
To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Elucidating Changes in Astrocyte Subpopulations Associated With Resistance to Alzheimers Disease Pathology in Multi-Ethnic Cohorts @ Columbia University Health Sciences
Project Summary/Abstract Alzheimer?s Disease (AD) is a progressive neurodegenerative disease, manifesting in brain pathology, neuropsychiatric symptoms, and cognitive decline. In general, confirmatory diagnosis of AD involves both pathological hallmarks (such as plaques and tangles) as well as clinically observed cognitive decline. Whereas most cases of patients with AD pathology show cognitive and clinical phenotypes, a subset of individuals have pathology suggestive of AD without the corresponding cognitive impairment. One possible explanation is that these ?resistant? individuals have compensatory mechanisms protecting their cognitive status from the presence of pathology. Recent work from single-nucleus RNA-sequencing on post- mortem human frontal cortex tissue suggests molecularly distinct subsets of astrocytes (a non-neuronal cell type in the brain) are differentially present in ?resistant? versus ?susceptible? (cognitively declined with pathology) individuals. However, this observation so far has been limited to a single brain region in a small sample of primarily Caucasian individuals. This proposal aims to corroborate and extend this finding by investigating astrocyte subpopulations, their molecular profiles, and their associations with other cell types in multiple regions of the brain in an ethnically diverse. Through a combination of single- nucleus RNA-sequencing, spatial transcriptomics, immunohistochemistry, and systems biology, we propose to create a map of the differential distribution of astrocyte subpopulations in ?resistant? and ?susceptible? individuals, their spatial relation to pathology and other cell types, and candidate genes and pathways that involved in astrocyte-mediated resistance to tau pathology. Ultimately, characterizing the association between specific astrocyte subpopulations, their interactions, and pathways involved in resistant individuals may identify therapeutic avenues to mitigate cognitive decline in the presence of AD pathology.
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0.942 |
| 2021 |
Christiano, Angela M (co-PI) [⬀]
Menon, Vilas
Phatnani, Hemali
Suh, Yousin (co-PI) [⬀] |
U54Activity Code Description:
To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
A Multi-Scale Atlas of Senescence in Diverse Tissue Types @ Columbia University Health Sciences
OVERALL: PROJECT SUMMARY Defining the molecular and cellular heterogeneity underlying senescent cell states is a critical knowledge gap in the field. The Columbia University Senescence Tissue Mapping (CUSTMAP) Center is uniquely poised to address this gap by creating a multi-scale atlas of senescence in diverse tissue types across the adult human lifespan. CUSTMAP is a highly collaborative effort that builds upon long-standing and established collaborations between Columbia University Irving Medical Center (CUIMC), The University of Edinburgh, New York University (NYU), and the New York Genome Center (NYGC). Using state-of-the-art spatial genomics technologies and leveraging our established experimental workflows and analytical pipelines, CUSTMAP will generate three- dimensional maps of senescent cells in tissues with vulnerability to age-related degenerative processes: the central nervous system (brain and spinal cord) and the skin. We will perform spatially resolved transcriptomics (ST), single-nucleus RNA-sequencing, and multiplexed proteomics using iterative indirect immunofluorescence imaging (4i) experiments in central nervous system (CNS) and skin tissues across the human lifespan, allowing for unprecedented genome-wide molecular characterization at single-cell resolution in space. CUSTMAP is structured around three scientific Cores, as well as an Administrative Core to support these integrated efforts. Human tissue samples characterized and collected through the Biospecimen Core (BIO) will be analyzed using the tools and techniques developed through the Biological Analysis Core (BAC) and Data Analysis Core (DAC), leading to detailed maps of senescent cells and their effects in human tissues at single-cell resolution. The success of CUSTMAP is predicated on access to a continuous supply of human tissues from healthy individuals across the lifespan. CUSTMAP investigators have access to post-mortem samples and prospective tissue collection from local resources at CUIMC as well as through established collaborations. Our unique geographic location in Upper Manhattan enables tissue acquisition from a local population of patients that is rich in racial and ethnic diversity. Thus, CUSTMAP is uniquely poised to obtain high-quality tissue from these diverse populations and apply cutting-edge multiomic approaches to build integrated 3D molecular atlases of senescent cells in CNS and skin tissues. Our approach provides a unique platform for driving transformative discoveries of novel molecular, cellular and regional correlates of age-related changes in cellular senescence in human tissues. The CUSTMAP workflow and computational tools are readily generalizable to other tissue types and can be efficiently shared with and deployed across the SenNet Consortium.
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0.942 |