Press Releases

Seattle - Oct 9, 2024

Benaroya Research Institute Awarded More Than $14 Million Across 11 Grants To Help Predict, Prevent, Reverse and Cure Immune System Diseases

Today, Benaroya Research Institute (BRI) announced 11 research grants totaling more than $14 million awarded in the first two quarters of 2024, including a $4.1 million grant to demonstrate how IgA autoantibodies play a significant role in the development of systemic lupus erythematosus (SLE). Another $4.2 million grant supports the study of a newly discovered pathway that protects cells against outer membrane damage caused by bacterial toxins or our own immune responses, with both funded by the National Institutes of Health (NIH).

The first $4.1 million NIH grant (R01AI185925) is led by BRI scientist Jessica Hamerman, PhD. Her research team is focused on how certain previously understudied antibodies in lupus can increase immune cell activity, which leads to a stronger inflammatory response. While most earlier lupus research focused on a type of antibody called IgG, this study reviewed the role of IgA and offers promising new directions for treatments.

“Together, these results highlight a new mechanism by which IgA autoantibodies contribute to SLE pathogenesis,” said Dr. Hamerman. “We’re excited to investigate the possibility of new clinical approaches that utilize IgA, which might be a better diagnostic for lupus development than the currently used IgG. It’s also possible that IgA and its receptor will be good targets for therapeutic intervention.”

Led by Adam Lacy-Hulbert, PhD, the $4.2 million NIH grant (R01AI77971) supports work following up on results from a genetic screen to find genes that would allow a human cell line to survive after exposure to a toxin from the bacteria Staphylococcus aureus, known as “alpha-toxin.” The research team previously identified a gene called LITAF that, when switched on, helps cells repair damage in their surface membranes caused by bacterial toxins. This is the first time this gene and pathway have been shown to be involved in the process of cell membrane repair, opening new avenues for research into how cells protect themselves against autoimmune attack.

“What is exciting to us is that this LITAF-mediated pathway is different from other pathways of membrane repair that have been described recently,” said Dr. Lacy-Hulbert. “It is activated by different signals and occurs at a different place in the cell. We think that the body may be able to activate this pathway during infection or stress to increase its defenses.”

In addition to these awards, BRI team members received nine other grants supporting research examining regulation of intestinal immunity, dermal fibroblast gene programs, and more.

“The human immune system is complex, which requires studying it from multiple angles, perspectives and disease areas,” said Jane Buckner, MD, president of BRI. “Our efforts collectively show BRI’s capacity to predict, prevent, reverse and cure diseases of the immune system.”

Details of the nine additional grants awarded to BRI in the first two quarters of 2024 include:

“Regulation of Intestinal Immunity and Repair by Integrins”

Adam Lacy-Hulbert, PhD, $2,919,460

Dr. Lacy-Hulbert’s work will determine the effects of the blockade of alpha v beta 6 integrins in the intestinal epithelium by studying epithelial cell cultures and mouse models. His team will test the hypothesis that loss of alpha v beta 6-mediated activation of transforming growth factor beta causes pre-clinical ulcerative colitis.

Sponsor: National Institutes of Health (R01DK136071)

“T Cell-Mediated Control of Dermal Fibroblast Gene Programs and Dysfunction in Scleroderma”

Peter Morawski, PhD, $476,575

Scleroderma is a disease of the connective tissue characterized by fibrosis of the skin and underlying organs. It has the highest mortality of all rheumatic conditions and no cure. This study will use single-cell spatial transcriptomics and innovative organotypic skin cultures to fill critical knowledge gaps in our current understanding of scleroderma and overcome existing technical hurdles in this field of research. Completion of this work will build a foundation for the generation of new hypotheses and advance a new organotypic culture model with the potential to reproduce in vivo fibroblast heterogeneity associated with tissue dysfunction in scleroderma.

Sponsor: National Institutes of Health (R21AI185642)

“T Cell Epigenomic Drivers of Disease Flares in Multiple Sclerosis”

Jane Buckner, MD, $476,575

Relapsing-remitting multiple sclerosis (RRMS) is an autoimmune disease in which CD4 T cells play a central role. Studying the epigenome of CD4 T cells in RRMS through the integration of genome-wide analysis of DNA methylation, open chromatin and histone modifications with RNA-sequencing data and variants identified by genome-wide association studies has the potential to bring clarity to the molecular processes that increase RRMS disease activity. This work will also advance our understanding of how changes in chromatin accessibility in the context of disease activity contributes to T cell pathogenicity and may reveal drivers of disease development.

Coinvestigators Karen Cerosaletti, PhD, and Arpit Mishra, PhD, will support this project.

Sponsor: National Institutes of Health (R21AI183670)

“Assessing and Mitigating T Cell Recognition of iPSC-Derived Endocrine Cells in Type 1 Diabetes”

Eddie James, PhD, $250,000

The goal of this project is to establish an improved strategy for beta-cell replacement therapy by examining key genes and pathways that are likely to compromise the fitness of replacement islet cells. Previous research has shown that specific enzymes promote autoimmune recognition of human islet cells in type 1 diabetes. This study will evaluate the activity of those enzymes and pathways in stem cells as they mature into replacement beta cells and test a gene-editing strategy to eliminate the negative effects of those pathways. Dr. James hypothesizes that stem cells engineered to lack expression of these stress-activated enzymes will have improved resilience, function, and ability to survive.

Sponsor: Breakthrough T1D (2-SRA-2024-1524-S-B)

“Systematic Dissection of IBD Non-Coding Risk Variants in Primary T Cells”

John Ray, PhD, $389,817

This study will use massively parallel reporter assays, allele-specific assays, and an assay for transposase-accessible chromatin sequencing to identify inflammatory bowel disease (IBD)-associated genetic variants that alter cis-regulatory region activity in primary CD4 T cells from IBD patients. Dr. Ray’s lab will confirm the top five IBD risk variants in each assay by using CRISPR base editing of variant risk alleles in T cells from people both with and without IBD.

Sponsor: Crohn's and Colitis Foundation (1158945)

“Systematic Dissection of Lupus Non-Coding Risk Variants in Primary B Cells”

John Ray, PhD, $299,918

To determine systemic lupus erythematosus (SLE) genetic variants that alter cis-regulatory activity, this research will test thousands of SLE-associated variants using two high-throughput genomic approaches: massively parallel reporter assays and an allele-specific assay for transposase-accessible chromatin sequencing. These approaches will identify likely disease-causal variants and assess major regulators that are disrupted by these variants using transcription factor motif analysis. Dr. Ray’s lab will also validate the top five SLE risk variants in each assay using CRISPR base editing of variant risk alleles in B cells from people both with and without SLE.

Sponsor: Lupus Research Alliance

“Targeting Subsets of Memory T Cells to Limit Neuroinflammation”

Estelle Bettelli, PhD, $726,000

Specific subsets of memory T cells have been identified in the central nervous systems (CNSs) of people living with multiple sclerosis (MS) and are suspected to contribute to disease progression. Primary goals of this study are to establish that these memory T cell subsets are harmful and determine how they cooperate with B cells. This will provide a better understanding as to if eliminating or removing specific subsets of memory T cells from the CNS will be beneficial for people living with MS. 

Dr. Bettelli’s research team aims to provide a foundation for new MS treatments by identifying unique markers on memory T cells and determining how they establish their residence in the CNS.

Sponsor: National Multiple Sclerosis Society (RG-2307-42130)

“Integrin Autoantibodies in the Pathogenesis of Ulcerative Colitis”

Adam Lacy-Hulbert, PhD, and James Lord, MD, PhD, $250,000

The goal of this study is to determine the effects of alpha v beta 6 autoantibodies on human and mouse intestinal epithelial cells.

Sponsor: Kenneth Rainin Foundation (20240045)

“2024 AAI Intersect Fellowship for Computational Scientists and Immunologists”

Jessica Hamerman, PhD, $63,852

This opportunity will support BRI’s Susana Orozco, PhD, a postdoctoral researcher in the Hamerman Lab, in undertaking one year of skill training in computational science. Hannah DeBerg, PhD, manager of BRI’s Bioinformatics Group, and Dr. Hamerman will provide mentorship to Dr. Orozco.

Throughout the course of the fellowship, Dr. Orozco and her mentors will conduct a research study utilizing single-cell RNA sequencing to capture different developmental states of monocytes that have been exposed to inflammation. Using mouse models, their team aims to understand how these monocytes differentiate into various inflammatory cells, and how the location of the monocytes affects their differentiation.

Sponsor: American Association of Immunologists

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About Benaroya Research Institute

Benaroya Research Institute (BRI) is a world leader in human immune system research. BRI works to advance the science that will predict, prevent, reverse and cure immune system diseases like allergies, asthma, cancer and autoimmune diseases. BRI accelerates discovery through laboratory breakthroughs in immunology that are then translated to clinical therapies. We believe that a breakthrough in one immune system disease can lead to progress against them all, and work tirelessly toward our vision of a healthy immune system for everyone. BRI is a world-renowned independent nonprofit research institute affiliated with Virginia Mason Franciscan Health and based in Seattle.

To learn more, visit benaroyaresearch.org and connect with us on Facebook, Instagram, Threads, LinkedIn, X and YouTube.