Benaroya Research Institute (BRI) announced eight research grants, totaling nearly $11.4 million, awarded in the latter half of 2024. These included a $3.6 million grant to investigate how a subset of regulatory cells are dysfunctional in controlling autoantibody production in patients with systemic lupus erythematosus (SLE). Another $3.8 million grant will study Type 1 diabetes (T1D) pathogenesis to guide timing and selection of early therapies. Both are funded by the National Institutes of Health (NIH).
The SLE grant is led by BRI scientist Steve Ziegler, PhD. His research of autoimmune diseases like SLE, which are characterized by the presence of autoantibodies, explores a subset of regulatory cells important for controlling antibody production. Specifically, FOXP3 is a critical gene that regulates the development and function of regulatory T cells (Tregs), which help prevent the immune system from attacking the body’s own tissues. Data suggests that an alternative version of FOXP3 may contribute to Treg dysfunction and increase susceptibility to autoimmune diseases, so the grant goal is to identify new pathways for therapeutic intervention.
The T1D grant is led by S. Alice Long, PhD, and will fund research to enable prevention by better understanding the process by which the disease develops and progresses. Specifically, this research will investigate clonal expansion of T cells in the first stage of T1D as a biomarker of disease activity to identify early preventative therapies. The investigative team also includes Karen Cerosaletti, PhD, and Peter Linsley, PhD.
“Given the complexity of the human immune system, we must continue to study it from multiple angles, perspectives and disease areas, as we strive toward prevention,” said Jane Buckner, MD, president of BRI. “These collective efforts demonstrate our potential at BRI to predict, reverse and cure diseases of the immune system, including SLE and T1D.”
In addition to these awards, BRI team members received six other grants supporting research examining colitogenic T cells, rheumatoid arthritis and more. Details of the six additional grants awarded to BRI in the last two quarters of 2024 include:
“Genetic Variants Guiding Pathogenicity of Colitogenic T Cells”
John Ray, PhD
Oliver James Harrison, PhD
$1,516,504
Drs. Ray and Harrison’s work will use cutting-edge, high-throughput methods to pinpoint causal genetic variants associated with inflammatory bowel disease (IBD), defining the genes and pathways variants impact. Their teams will accomplish this in primary pathogenic Th17 cells, a key IBD-relevant cell type, to identify how risk variants affect gene expression, migration and function.
Sponsor: National Institutes of Health (R01DK140972)
“Supplement: Dissecting T and B Cell Dysregulation in People With Down Syndrome”
Bernard Khor, MD, PhD
$453,873
The proposed research is relevant to public health because it interrogates mechanisms of CD4+ T cell
dysregulation and of impaired vaccine response in people with Down syndrome. This knowledge would establish the foundation to identify therapies to mitigate immune aging and impaired vaccine response in people, both with and without Down syndrome, with likely utility across a broad spectrum of immune-related conditions.
Sponsor: National Institutes of Health (R01AI166835-03S1)
“Characterizing Circulating and Visceral T Cells Specific for the Autoantigen Integrin αvβ6 in Ulcerative Colitis”
James Lord, MD, PhD
$468,777
People with the chronic inflammatory bowel disease ulcerative colitis (UC) were recently found to uniquely make antibodies to a complexed pair of proteins (integrins αv and β6) on the epithelial cells that line their intestines, even years before diagnosis. Dr. James Lord and his team have experience with an assay that will help find the T cells behind these antibodies in the blood, colons and lymph nodes archived from people with and without UC to learn fundamental truths about how the intestinal immune system is regulated in humans.
Sponsor: National Institutes of Health (R21AI188483)
“Supplement: Proteomic Analysis of Hydroxychloroquine Prevention Trials in T1D, RA and SLE”
Jane Buckner, MD
S. Alice Long, PhD
$265,178
Drs. Jane Buckner and S. Alice Long will investigate the immune mechanisms contributing to the transition from sub-clinical autoimmunity to clinical autoimmune disease, focusing on this transition in individuals at-risk for T1D, rheumatoid arthritis and systemic lupus erythematosus.
Sponsor: National Institutes of Health (U01AI176320-02S1)
“Long-Read Approaches To Identify Coding, Non-Coding, and Structural Variation That Contributes to T1D Risk”
Eddie James, PhD
$150,000
T1D results from destruction of pancreatic beta cells by autoreactive T cells. This research proposes to apply a new long read DNA sequencing and analysis strategy developed by Base5 Genomics (Mountain View, California) to identify novel genetic features that contribute to T1D risk. An improved understanding of genetic risk would increase the ability to identify individuals with elevated risk and may reveal new pathways underlying T1D.
Sponsor: Breakthrough T1D, JDRF (1-SRA-2024-1617-S-B)
“Mechanisms of Autoantibody Reversion in At-Risk Subjects”
Cate Speake, PhD
$1,078,232
Dr. Cate Speake and team showed that among people at-risk for T1D, a rare group who have multiple autoantibodies can lose these autoantibodies. They then demonstrated that loss of autoantibodies – or “reversion” – was associated with reduced rate of T1D disease progression. Here, her team aims to define the mechanistic drivers of loss of autoantibodies in this same cohort of people at-risk for type 1 diabetes, to understand why these individuals were able to naturally evade disease progression.
Sponsor: The Leona M. and Harry B. Helmsley Charitable Trust (#2402-08189)
For more information on BRI and its research efforts, visit benaroyaresearch.org.
