U01DK143488
Cooperative Agreement
Overview
Grant Description
Discovery of pathways and molecular mediators of early T1D pathogenesis using spatial multi-omics - Project summary/abstract
Type 1 diabetes (T1D) is a complex, devastating autoimmune disease with a slow progression of pancreatic beta-cell dysfunction (e.g., a decline of first phase insulin release occurs over several years) before the clinical onset of T1D.
Unfortunately, we still have a lack of knowledge on the molecular mechanisms of early T1D pathogenesis.
The long-term goal of this project is to gain a detailed understanding of in situ molecular mechanisms of early human T1D development through advanced spatial omics profiling of human islet microenvironments within clinical tissue specimens and functional studies of novel mediators.
Our research plan centers on the critical role of human islet microenvironments in disease progression and the observations of substantial intra-donor heterogeneity of islet microenvironments (in both pre-diabetic and recent-onset subjects) for unraveling progression information.
Our hypothesis is that pathways or molecular mediators of disease progression (otherwise unattainable without longitudinal samples) can be uncovered through advanced spatial multi-omics profiling of individual islet microenvironments in the context of intra-donor heterogeneity for each pre-T1D or new-onset T1D donor.
Spatial omics data on individual islet microenvironments will unravel “pseudo-time” progression of islet dysfunction within each donor.
Common pathways and molecular mediators across multiple donors will be identified for functional studies.
Our plan is to pursue spatial multi-omics profiling of islet microenvironments at two different resolutions.
Aim 1 will focus on characterizing intra-donor heterogeneity across individual islet microenvironments at the ROI (region of interest) level with each islet microenvironment as a ROI.
Pseudo-time progression and its underlying pathways will be uncovered through correlation analysis with pathology scores for each ROI.
One example of the pathology scores is the immune signature (a 20-protein panel discovered from our preliminary studies) whose expression levels can serve as a pathology score for each islet microenvironment.
Aim 2 will characterize islet microenvironments at the single cell resolution with the goal to reveal cellular niches of specific type of islet dysfunction (e.g., insulitis or β-cell loss).
Aim 3 will explore the functional significance of identified molecular mediators through assessing their roles in cellular communication and beta cell survival using human islet/β-cells and acinar cell co-cultures.
Our approach is enabled by mass spectrometry-based spatial proteomics, spatial transcriptomics, and mass spectrometry imaging (MSI) for lipidomics and extracellular matrix (ECM)-omics.
Statement of impact: We anticipate this project will establish first-of-its-kind spatial molecular resources on human islet microenvironments in early stages of T1D development, provide evidence of novel in situ molecular mediators and biological processes from human patient samples, and contribute towards the development of novel therapeutic intervention strategies.
These innovative approaches and data resources will also likely enhance the overall impact of the current resources from the Human Islet Research Network (HIRN) and enable further collaborations with other investigators within the T1D community.
Type 1 diabetes (T1D) is a complex, devastating autoimmune disease with a slow progression of pancreatic beta-cell dysfunction (e.g., a decline of first phase insulin release occurs over several years) before the clinical onset of T1D.
Unfortunately, we still have a lack of knowledge on the molecular mechanisms of early T1D pathogenesis.
The long-term goal of this project is to gain a detailed understanding of in situ molecular mechanisms of early human T1D development through advanced spatial omics profiling of human islet microenvironments within clinical tissue specimens and functional studies of novel mediators.
Our research plan centers on the critical role of human islet microenvironments in disease progression and the observations of substantial intra-donor heterogeneity of islet microenvironments (in both pre-diabetic and recent-onset subjects) for unraveling progression information.
Our hypothesis is that pathways or molecular mediators of disease progression (otherwise unattainable without longitudinal samples) can be uncovered through advanced spatial multi-omics profiling of individual islet microenvironments in the context of intra-donor heterogeneity for each pre-T1D or new-onset T1D donor.
Spatial omics data on individual islet microenvironments will unravel “pseudo-time” progression of islet dysfunction within each donor.
Common pathways and molecular mediators across multiple donors will be identified for functional studies.
Our plan is to pursue spatial multi-omics profiling of islet microenvironments at two different resolutions.
Aim 1 will focus on characterizing intra-donor heterogeneity across individual islet microenvironments at the ROI (region of interest) level with each islet microenvironment as a ROI.
Pseudo-time progression and its underlying pathways will be uncovered through correlation analysis with pathology scores for each ROI.
One example of the pathology scores is the immune signature (a 20-protein panel discovered from our preliminary studies) whose expression levels can serve as a pathology score for each islet microenvironment.
Aim 2 will characterize islet microenvironments at the single cell resolution with the goal to reveal cellular niches of specific type of islet dysfunction (e.g., insulitis or β-cell loss).
Aim 3 will explore the functional significance of identified molecular mediators through assessing their roles in cellular communication and beta cell survival using human islet/β-cells and acinar cell co-cultures.
Our approach is enabled by mass spectrometry-based spatial proteomics, spatial transcriptomics, and mass spectrometry imaging (MSI) for lipidomics and extracellular matrix (ECM)-omics.
Statement of impact: We anticipate this project will establish first-of-its-kind spatial molecular resources on human islet microenvironments in early stages of T1D development, provide evidence of novel in situ molecular mediators and biological processes from human patient samples, and contribute towards the development of novel therapeutic intervention strategies.
These innovative approaches and data resources will also likely enhance the overall impact of the current resources from the Human Islet Research Network (HIRN) and enable further collaborations with other investigators within the T1D community.
Awardee
Funding Goals
NOT APPLICABLE
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
Washington
United States
Geographic Scope
State-Wide
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 288% from $802,595 to $3,112,201.
Battelle Memorial Institute was awarded
Early T1D Pathogenesis Unveiled: Spatial Multi-Omics Discovery
Cooperative Agreement U01DK143488
worth $3,112,201
from the National Institute of Diabetes and Digestive and Kidney Diseases in May 2026 with work to be completed primarily in Washington United States.
The grant
has a duration of 4 years and
was awarded through assistance program 93.847 Diabetes, Digestive, and Kidney Diseases Extramural Research.
The Cooperative Agreement was awarded through grant opportunity Discovery of Early Type 1 Diabetes Disease Processes in the Human Pancreas [HIRN Consortium on Beta Cell Death and Survival (CBDS)] (U01 Clinical Trial Not Allowed).
Status
(Ongoing)
Last Modified 7/6/26
Period of Performance
5/1/26
Start Date
4/30/30
End Date
Funding Split
$3.1M
Federal Obligation
$0.0
Non-Federal Obligation
$3.1M
Total Obligated
Activity Timeline
Transaction History
Modifications to U01DK143488
Additional Detail
Award ID FAIN
U01DK143488
SAI Number
U01DK143488-3248535895
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Nonprofit With 501(c)(3) IRS Status (Other Than An Institution Of Higher Education)
Awarding Office
75NK00 NIH National Institute of Diabetes and Digestive and Kidney Diseases
Funding Office
75NK00 NIH National Institute of Diabetes and Digestive and Kidney Diseases
Awardee UEI
CWKJEXDG79A7
Awardee CAGE
1A453
Performance District
WA-90
Senators
Maria Cantwell
Patty Murray
Patty Murray
Modified: 7/6/26