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Integrating Spatial Multi-omics and Clinical Covariates to Identify Mechanisms of Disease in ALS-FTD

Award Number: R01NS118183
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Integrating Spatial Multi-omics and Clinical Covariates to Identify Mechanisms of Disease in ALS-FTD - Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a fatal and untreatable disease spectrum that is unified by a diverse presentation of TDP-43 aggregation across central nervous system (CNS) tissue. Up to 50% of patients with motor dysfunction also present with cognitive deficits and 15% have frank FTD, but the molecular mechanisms underlying diverse clinical and pathological presentations remain poorly understood. In our recent work, we have shown that the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) is a good clinical predictor of extra-motor TDP-43 pathology. Specifically, ECAS subdomain scores correlate with the distribution of TDP-43 inclusions in brain regions corresponding to the affected cognitive domains. However, the presence of TDP-43 pathology in a region is not predictive of cognitive deficits associated with that region. We posit that there may be other, more sensitive, neuropathological correlates of cognitive involvement that remain to be identified, and hypothesize that additional pathological features--including nucleocytoplasmic protein mislocalization, perturbations in gene expression, and dysfunctional cell-cell interactions--may correlate more closely with domain-specific cognitive impairment corresponding to a particular region of the frontal cortex. We will test this hypothesis through a comprehensive multi-omic analysis of post- mortem tissue that identifies 1) how differences in cell type-specific subpopulations and intercellular interactions between ALS-FTD cases and controls relate to protein aggregation and mislocalization and 2) how these differences relate to cognitive impairment in ALS-FTD. We will accomplish these goals using spatially resolved proteomic (Aim 1) and transcriptomic (Aim 2) measurements to analyze clinico-pathologically stratified dorsolateral prefrontal cortical tissue samples (specifically, Brodmann areas BA44 and BA46) from cognitively impaired ALS patients and age/gender matched 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. We have previously implemented Spatial Transcriptomics (ST) on the spinal cord to identify regional differences within subpopulations of various cell types that vary as a function of disease dynamics. These data will be directly tied to measures of 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 disease burden (Aim 2). Finally, we will implement highly multiplexed immuno-imaging to validate our findings in an independent ALS- FTD cohort (Aim 3). Our integrated analysis across experimental modalities (single cell RNA-seq, spatial transcriptomics, multiplexed imaging and proteomics) will yield an unprecedented view of disease pathology and elucidate neurotrophic and neurotoxic functions that are coordinated within and across different cell populations.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $751,277 )
2024	2024	NEW YORK GENOME CENTER, INC.	101 AVENUE OF THE AMERICAS FL 7	NEW YORK	NY	10013	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/1/2024	NON-COMPETING CONTINUATION	$751,277
														Subtotal = $751,277

Issue Date FY: 2023 ( Subtotal = $767,453 )
2023	2023	NEW YORK GENOME CENTER, INC.	101 AVE OF THE AMERICAS FL 7	NEW YORK	NY	10013	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/7/2023	NON-COMPETING CONTINUATION	$767,453
														Subtotal = $767,453

Issue Date FY: 2022 ( Subtotal = $787,330 )
2022	2022	NEW YORK GENOME CENTER, INC.	101 AVE OF THE AMERICAS FL 7	NEW YORK	NY	10013	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/1/2022	NON-COMPETING CONTINUATION	$787,330
2022	2021	NEW YORK GENOME CENTER, INC.	101 AVE OF THE AMERICAS	NEW YORK	NY	10013	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	10/27/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $787,330

Issue Date FY: 2021 ( Subtotal = $802,118 )
2021	2021	NEW YORK GENOME CENTER, INC.	101 AVE OF THE AMERICAS	NEW YORK	NY	10013	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/26/2021	NON-COMPETING CONTINUATION	$802,118
														Subtotal = $802,118

Issue Date FY: 2020 ( Subtotal = $867,241 )
2020	2020	NEW YORK GENOME CENTER, INC.	101 AVE OF THE AMERICAS	NEW YORK	NY	10013	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/3/2020	NEW	$867,241
														Subtotal = $867,241

Grand Total All Awards = $3,975,419

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Integrating Spatial Multi-omics and Clinical Covariates to Identify Mechanisms of Disease in ALS-FTD

Award Number: R01NS118183

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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