Uncovering biophysical determinants of AL amyloidosis through high-throughput stability and aggregation measurements
Active Project Grant Awarded Last action
- Award ID
- F31DK149863
- Recipient
-
Northwestern University UEI KG76WYENL5K1
- Awarding agency
-
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $45,327
Award facts
- Assistance listing
- 93.847 Diabetes, Digestive, and Kidney Diseases Extramural Research
- Completion date 0% complete
- Place of performance
- Chicago, IL 60611, USA
Award details come from USAspending.gov.
Description
- Abstract
- Amyloid light-chain amyloidosis (AL amyloidosis) is the most common form of amyloidosis and is caused by the deposition of misfolded immunoglobulin light chains as amyloid fibrils. This disease affects 3,000-5,000 new patients per year in the US, primarily affecting the heart, kidneys, and liver and leading to progressive organ failure and death. A quarter of patients DIE within a year of diagnosis, but treatment outcomes improve when the disease is caught early, before extensive amyloid deposition and cardiac involvement. However, early identification of amyloid-forming light chain variants is difficult because of the large number of possible antibody light chain sequences in the human population. Millions of unique light chain variable domain sequences have been recorded across several public databases and many more exist in the human population; only a small fraction are pathogenic. This proposal aims to identify molecular features that drive light chain pathogenicity by (1) testing the hypothesis of a link between folding stability and amyloidosis, and (2) determining sequence properties that confer stability and aggregation to light-chain variable domains. This project will apply high-throughput assays to measure folding stability and aggregation propensity across a large set of immunoglobulin light-chain variable domains. Using our recently developed cdna-display proteolysis assay, I will quantify folding stability for 1,652 AL-base-annotated variants and ~200,000 unannotated human variants. I will also measure aggregation propensity for the same variants using a high-throughput nucleation kinetics assay. Integrating these biophysical measurements and pathogenic annotations using computational modeling and machine learning will clarify the relationship between stability, aggregation, and amyloidogenic risk. Understanding the sequence determinants of light chain stability and amyloid fibril formation will support earlier diagnosis, improve risk stratification, and guide therapeutic development for AL amyloidosis.
Quick answers
Who received award F31DK149863?
F31DK149863 was awarded to Northwestern University by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on February 14, 2027.
How much is award F31DK149863 worth?
$45,327 has been obligated on F31DK149863.
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