# Spatially Resolved Dynamics of Molecular Pathology and Intercellular Interactions in Amytrophic Lateral Sclerosis

> **NIH NIH R01** · NEW YORK GENOME CENTER · 2022 · $567,750

## Abstract

Project Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease in which the loss of
upper (primary motor cortex, M1) and lower (spinal cord, SC) motor neurons (MNs) ultimately leads to total
paralysis. MN loss in ALS involves cell autonomous and non-cell autonomous activities in multiple cell types of
the M1 and SC, the organization of which are well understood. However, there remain 4 major gaps in our
knowledge: 1) How ALS-associated molecular pathology in the various cell types of the M1 relates to those in
the SC; 2) How subpopulations of specific cell types are spatially arranged in these two regions; 3) How
subpopulations of different cell types are organized in higher-order ensembles; and 4) How the coordinated
behavior of these ensembles relates to disease-associated molecular pathology (e.g., pathognomonic
inclusions). Towards addressing these questions, we propose to develop a spatially resolved multi-omics
catalog of cellular subpopulations in the M1 and SC of patients with ALS and healthy controls. By using
a combination of approaches to simultaneously map the spatial transcriptome and proteome of all interacting
cellular subpopulations in these regions, our aim is to elucidate the origins and temporal dynamics of inter- and
intra-cellular activities that may reveal novel diagnostic and therapeutic targets for ALS. Our overarching
hypothesis is that ALS pathology stems from dysfunctional MN-glial interactions, and that this predictably differs
in the M1 and SC in accordance with patient symptomatology. To address this hypothesis, we propose to use
spatially resolved transcriptomic and proteomic measurements to study intact human postmortem tissue from
patients stratified by clinical presentation (i.e., site of initial symptom presentation, bulbar or lower limb). We have
previously implemented Spatial Transcriptomics on mouse and human SC to identify regional differences within
subpopulations of various cell types that vary as a function of disease dynamics. Here, we propose to build upon
our existing human study, and for the first time, develop a spatially resolved multi-omics dataset at scale and in
the context of disease in matched human postmortem M1 and SC samples (Aim 1), to enable simultaneous
exploration of upper and lower motor neurons in the context of intact tissue. These data will be directly tied to
measures of ALS pathology (e.g., pathognomonic inclusions). To integrate and analyze relationships between
data across modalities, we will develop a computational framework for harmonized analysis of multi-modal, multi-
omic measures of ALS disease burden (Aim 2). Finally, we will implement highly multiplexed immuno-imaging
to validate top gene candidates generated in Aim 1 at a single-cell level in situ (Aim 3). We expect to obtain an
unmatched view of cellular interactions in the postmortem ALS M1 and SC, and to be able to directly link such
interactions to features of ALS patholog...

## Key facts

- **NIH application ID:** 10322138
- **Project number:** 5R01NS116350-03
- **Recipient organization:** NEW YORK GENOME CENTER
- **Principal Investigator:** Christopher Jackson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $567,750
- **Award type:** 5
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322138

## Citation

> US National Institutes of Health, RePORTER application 10322138, Spatially Resolved Dynamics of Molecular Pathology and Intercellular Interactions in Amytrophic Lateral Sclerosis (5R01NS116350-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10322138. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*