# The Aging vs Disease Trajectory Trees of CNS Cell Types Based on Simultaneous Single Nuclear Global Genomic Analyses

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $393,750

## Abstract

ABSTRACT
Here we propose a Supplement to the research proposed in the parent grant Combinatorial regulation of the
enhancer codes in senescence to perform a logical extension of our initial Specific Aims regarding cellular
aging/senescence to achieve initial insights into the distinction between these events and distinct pathological
causal features in each CNS cell type that may represent the underlying mechanisms underlying sporadic
Alzheimer’s Disease (AD). The Specific Aims of the initial grant employed and developed biostatistical tools
relevant to cellular aging and replicative senescence, including an examination of underlying epigenomic
alterations and enhancer activation codes ultimately leading to cellular senescence approaches and proposed
application of single cells approaches. Appling these specific aims/approaches is particularly suitable for
enhancing our understanding of the potential initial causal events that eventuate in clinical sporadic AD, an aging-
associated disease affecting both men and, to a greater extent, women. In concert with the original Aim of
understanding the molecular basis for enhancer-mediated programs of cellular aging and senescence, in this
Supplement, we propose to extend our original Specific Aims to uncover the enhancer program underlying the
aging events in each CNS cell type, to permit examination of the central question whether the altered enhancer
and transcriptome changes in AD in each cell type represent a trajectory distinct from the normal aging-related
alterations in these cell types. We hypothesize that, while each cell type will, of course, exhibit specific features
of enhancer activation characteristic of aging and even cellular senescence, as we have uncovered in the parent
grant, AD represents a distinct trajectory for these cell types. This Supplement is licensed by our ability by our
development of the technology to perform simultaneous quantitation of single nucleus (sn) RNA-seq and
snATAC-seq using archival samples stored at the brain bank of the Shiley-Marcos Alzheimer's Disease
Research Center (ADRC) at UCSD. We have carefully piloted this approach to ensure that we are technically
able to obtain high quality data and that all of the proposed informatic pipelines and our ability to successfully
aggregate such massive data sets is fully established. The Supplement would license our ability to scale the
analysis to obtain data sets capable of generating statistically significant results and, therefore, informative
conclusions, which can be ultimately be further validated by imputation from available data bases and using
hiPSCs to generate specific cell types for validating transcriptional analyses. Our overarching goal in this
Supplement is to apply the described technologies and new informatic approaches to a sufficient number of
archived specimens to permit formulating the actual transcription factors and pathways that distinguish initiation
of the AD process in specific CNS cell typ...

## Key facts

- **NIH application ID:** 10115254
- **Project number:** 3R01AG061521-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** MICHAEL G ROSENFELD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $393,750
- **Award type:** 3
- **Project period:** 2019-09-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115254

## Citation

> US National Institutes of Health, RePORTER application 10115254, The Aging vs Disease Trajectory Trees of CNS Cell Types Based on Simultaneous Single Nuclear Global Genomic Analyses (3R01AG061521-02S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10115254. Licensed CC0.

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