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NIH grant 1R03DE036362-01: Spatial Dissection of Pathogenic Endotypes and Therapeutic Mechanisms in Sjögren's Disease
Institute: {'code': 'DE', 'abbreviation': 'NIDCR', 'name': 'National Institute of Dental and Craniofacial Research', 'admin_org_id': '12500070', 'admin_funding_url': ''}. PI: Jinze Liu. Award: $310500.
Start: 2026-08-28T00:00:00.
Sjögren's Disease (SjD) remains a significant clinical challenge as a common systemic autoimmune disease
that lacks effective, disease-modifying therapies, a problem largely driven by its profound molecular
heterogeneity which has historically confounded clinical trials. Although key pathogenic cell types have been
identified, a critical knowledge gap persists in understanding how these cells are spatially organized to
orchestrate the complex process of tissue damage. This proposal addresses this gap by aiming to define the
"pathogenic communication architecture" that may drive the disease. Our work is guided by the central
hypothesis that SjD pathogenesis is driven by a spatially-organized communication network, and that features
of this architecture, present before treatment, may be associated with a patient's response to targeted therapy.
The scientific premise is that by first defining these pathogenic cellular ecosystems, we can then use our
unique access to a longitudinal dataset from a completed randomized, controlled trial of the JAK inhibitor,
tofacitinib (NCT04496960), to investigate which architectural features are modulated during a successful
therapeutic response. Given the significant expense of generating new single-cell and spatial omics data, the
goal of this R03 application is to establish the necessary computational framework and generate the key
preliminary data to effectively design and power a future, larger-scale clinical trial. To achieve this, we will
pursue two highly integrated aims. In Aim 1, we will construct a foundational, harmonized single-cell atlas
by integrating large, publicly available datasets to test our working hypothesis that SjD pathology is sustained
by recurrent, spatially-defined "cellular neighborhoods" where specific subtypes of pathogenic immune cells
and pro-inflammatory fibroblasts physically co-localize. This atlas will enable the definition of data-driven
molecular endotypes and a preliminary exploration of molecular features associated with sex-based
disparities, serving as the foundation for integration with high-resolution spatial transcriptomics to
validate these findings within the tissue microenvironment. In Aim 2, leveraging the architectural
framework from Aim 1, we will test our working hypothesis that the pre-treatment molecular state and
spatial arrangement of these pathogenic cellular neighborhoods can help distinguish future responders
from non-responders to JAK inhibition. This will involve analyzing paired pre- and post-treatment biopsies to
characterize on-treatment cellular changes and conducting a hypothesis-generating analysis of the pre-
treatment biopsies to identify strong candidate biomarkers that could warrant investigation in larger cohorts.
This approach is supported by our multi-disciplinary team, co-led by a computational biologist and a
physician-scientist, which combines long-term clinical expertise in SjD with extensive experience in
building single-cell atlases, developing novel spatial multi-omics methods, and establishing reproducible
bioinformatics pipelines. Ultimately, this work seeks to bridge discovery and clinical practice by generating
strong candidate biomarkers for patient stratification, providing the essential preliminary work needed to de-risk
and power the cost-effective design of a future, larger clinical trial.document fetched 2026-09-06 02:47