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TOPSPIN - Top-dOwn Proteomic Signatures for cirrhosis ProgressIoN

Award Number: R01DK146179
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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TOPSPIN - Top-dOwn Proteomic Signatures for cirrhosis ProgressIoN - PROJECT SUMMARY Liver cirrhosis affects 2-7 million adults in the US, has doubled over the last decade, and is associated with high rates of healthcare utilization and high costs of care. Patients with cirrhosis are at risk for liver related complications, particularly hepatic decompensation (e.g., ascites, hepatic encephalopathy, gastrointestinal bleeding) which has high morbidity, low quality of life and increased mortality. Early intervention with specialty care is essential. Presently, we lack effective tools to identify the subset of patients with cirrhosis who are at high risk for decompensation, which would enable prioritization of preventative interventions and increase priority access to specialty care, thus improving overall outcomes. Particularly, we lack validated markers that predict the transition from compensated to decompensated cirrhosis. “Top-down” proteomics (TDP) allows for the direct characterization of proteoforms, which are the molecular variants of proteins. In our preliminary work, a TDP analysis of plasma from a cohort of 30 patients showed that progressive stages of liver cirrhosis could be determined by their patterns of differentially expressed proteoforms (DEPs). We identified 209 DEPs across three stages of cirrhosis (compensated, compensated with portal hypertension, and decompensated). Enrichment analyses of the DEPs suggested that they are involved in several hematological and immunological processes known to be impacted by cirrhosis progression. These data are cross sectional, and prospective data are required to fully understand which changes occur at what time during the progression from compensated cirrhosis to decompensated cirrhosis. To this end, this ancillary study to the NIDDK sponsored Liver Cirrhosis Network (LCN) and approved by the LCN, will examine plasma from 200 of the 1,200 prospectively enrolled and well phenotyped patients with cirrhosis that were prospectively followed for 36 months. We hypothesize that disease progression in patients with compensated cirrhosis is associated with modification of abundant plasma proteoforms associated with coagulation and lipid metabolism. Plasma proteoform composition will provide a sensitive window into early changes in liver status, preceding physiological markers of decompensation, and will allow for risk stratification of decompensation in patients with cirrhosis. The specific aims are: (Aim 1) Provide the molecular basis for understanding personalized progression of liver cirrhosis and selection of candidate markers. (Aim 2) Identify candidate proteoforms associated with probability of decompensation. (Aim 3) Integrate diverse domains of data to identify proteoform changes that precede the functional changes that occur during decompensation. This work will yield fundamentally new knowledge on the molecular foundations of decompensation as reflected in plasma and will advance future work in management and treatment of cirrhosis.


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: 2026 ( Subtotal = $683,963 )
2026	2026	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/19/2026	NEW	$683,963
														Subtotal = $683,963

Grand Total All Awards = $683,963

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TOPSPIN - Top-dOwn Proteomic Signatures for cirrhosis ProgressIoN

Award Number: R01DK146179

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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