# Systematic modeling and prediction of cell-type-specific and spatiotemporal crosstalk pathways in Alzheimer's Disease

> **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2024 · $790,802

## Abstract

Abstract
Alzheimer’s disease (AD) affects more than 50 million people worldwide but there is no clear therapeutic option
for the patients. For last two decades, AD research has been focusing on a neuron-centric biochemical process
that leads to synaptic deficits and neuronal degeneration. However, recent failures in clinical trials clearly
demonstrate a gap in knowledge in our current understanding of AD pathogenesis and call for studies that lead
to unbiased and holistic understanding of disease pathways in different types of brain cells. This project aims to
tackle this important and urgent issue by combining a computational systems biology platform Single-Cell
Resolution Brain Interactome (SCRBI) Explorer, 3D human Alzheimer’s-in-a-dish models, and the publicly
available multiple-omics AD databases through NIH-funded AMP-AD portal. We will expand the knowledge
base of SCRBI Explorer to handle single cell transcriptomic and multiple omics profiles from 3D cell models
and human brain tissues, which can detect on multiple layers of neuron-glia and glia-glia crosstalk pathways
via ligand-receptor interactions, cytokine/chemokine signaling, intracellular signaling activities, and
transcriptional activation. The central hypothesis is that the combined use of multi-cellular systems biology
modeling and 3D human AD cellular models will identify AD-specific neuron-glia and glia-glia crosstalk
pathways, which would provide novel therapeutic targets for drug repositioning. We will test this hypothesis by
pursuing three specific aims: 1) Develop a multi-cellular crosstalk model to uncover altered neuron-glia and
glia-glia crosstalk pathways in AD, 2) identify and validate AD-specific neuron-glia and glia-glia crosstalk
pathways that are enriched in 3D human AD cellular models and human AD brain cells, and 3) evaluate the
therapeutic potential of neuron-glia and glia-glia crosstalk using 3D human neural cell culture models of AD.
The potential impact of this proposal is high because the proposed study, if successful, will provide a unique
integrated bioinformatics tool to unbiasedly identify neuron-glia and glia-glia crosstalk pathways in AD and
even other neurodegenerative diseases. More importantly, it will provide novel therapeutic targets based on
altered neuron-glia interaction pathways in AD and open up a new vista for drug repositioning targeting cell-cell
interactions in the brain of AD patients.

## Key facts

- **NIH application ID:** 10830941
- **Project number:** 5R01AG071496-04
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Doo Yeon Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $790,802
- **Award type:** 5
- **Project period:** 2021-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830941

## Citation

> US National Institutes of Health, RePORTER application 10830941, Systematic modeling and prediction of cell-type-specific and spatiotemporal crosstalk pathways in Alzheimer's Disease (5R01AG071496-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10830941. Licensed CC0.

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