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24 grants worth up to $9.1M match your search

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open

NIH

Project Summary Background and Innovation: Glucagon has long been recognized as an insulin counterregulatory hormone. However, more recent studies have revealed that it also activates glucagon-like peptide-1 receptors (GLP1R) on beta cells to enhance glucose-dependent insulin secretion. Harnessing glucagon for diabetes therapy has been challenging because of its opposing hyperglycemic and hypoglycemic effects in the liver and islet. Remarkably, we have discovered a transcriptional network controlled by BCL6 in the liver which causes a unique form of selective glucagon resistance and confers favorable anti-diabetic effects in both the liver and islet. Our first aim will elucidate the impact of BCL6 on glucagon action and metabolism in the liver. Our second aim will determine the inter-organ ramifications of this liver pathway on islet signaling and insulin secretion. Finally, in our third aim we will test a liver specific Bcl6 knockdown as a therapeutic for type 2 diabetes mellitus. Our study will elucidate this previously unknown liver pathway using a broad combination of biochemical assays, epigenetic and gene expression analysis, and physiologic testing with unique mouse models and primary cells, including both gain- and combinatorial loss-of-function genetic strategies to reveal interorgan communication. Further, we will use state-of-the-art hepatocyte-directed antisense oligonucleotides (ASOs) for preclinical testing to establish the benefits of targeting BCL6 for diabetes and obesity therapy. Collectively, these experiments will provide deep mechanistic and physiologic understanding of glucagon and therapeutic manipulation of glucagon signaling, setting the stage for clinical development and testing of analogous hepatocyte-directed therapy for humans. Significance and Impact to Veterans Healthcare: Type 2 diabetes mellitus afflicts 25% of Veterans, and hyperglycemia and diabetes-related complications remain inadequately controlled with current therapies. Our findings will elucidate a new target for treating type 2 diabetes mellitus and obesity-related disease. Exploiting this target will enable therapies to leverage both the benefits of glucagon blockade in the liver and glucagon agonism in the islet to improve glycemic control. Moreover, we will establish the efficacy of targeted nucleic acid-based therapy to specifically exploit the liver BCL6 pathway for therapy of type 2 diabetes mellitus in pre-clinical models. Path to translation/implementation: The work in this proposal will be foundational in establishing BCL6 as a new target for diabetes. We will test antisense oligonucleotides targeted specifically to hepatocyte BCL6 in mice. Success in our pre-clinical model can then be advanced for human translation by adapting the antisense oligonucleotides to knockdown the human BCL6 ortholog for future clinical testing in humans with type 2 diabetes mellitus.

2030-03-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Leveraging human genetics to decipher B cell activation dysregulation in lupus

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NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY The overarching goal of this research is to elucidate the genetic underpinnings of B cell activation dysregulation in lupus, a leading cause of morbidity among youth in the United States. By decoding the complex interactions at the genetic and cellular levels, this project aims to unveil new targets for therapeutic intervention, ultimately reducing the disease burden. The genetic contribution to lupus is high and genome-wide association studies (GWAS) have found >150 risk variants for lupus. However, linking GWAS risk variants to mechanism has been achieved for only a small proportion of loci given most of the likely causal variants are non-coding. Our preliminary data identified a relevant B cell activation condition at which a great proportion of lupus risk variants are likely exerting their regulatory effects. We have further preliminary data focused on 2 specific lupus risk loci, representing two classes of mechanisms by non-coding risk variants: one class that affects gene expression levels of the target gene, and one that affects isoform usage of the target gene. For each locus we plan to establish the most likely causal risk variant, the mechanism by which the risk allele causes dysregulation, and the function of the target gene in B cell differentiation. We plan to study these aspects in both healthy subjects and lupus patients, and by utilizing advanced technologies including single cell profiling, CRISPR methods, tonsil organoids and long read RNA sequencing. Furthermore, we plan to uncover additional loci with differential isoform usage driven by lupus risk loci. Overall, this research is poised to provide critical insights into the molecular mechanisms of lupus, offering potential strategies for targeted treatment. By enhancing our understanding of B cell biology in the context of chronic autoimmune disease, our findings could lead to the prioritization of novel genetic targets, laying the groundwork for innovative therapeutic approaches in lupus and other immune-mediated diseases.

Up to $906K

2031-04-30

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Leveraging Hydroides elegans to Uncover NfKb Pathway Roles in Innate Immune Discrimination

open

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY NF-κB is a central regulator of innate immune signaling, orchestrating processes like inflammation, cell survival, and tissue remodeling in response to microbial stimuli. Despite its essential role, the mechanisms by which NF-κB mediates beneficial responses (e.g., tissue homeostasis) versus pathological ones (e.g., chronic inflammation and cell death) remain unresolved. Dysregulation of NF-κB signaling is a hallmark of inflammatory bowel disease (IBD), where persistent inflammation damages the intestinal lining and leads to debilitating symptoms. Current treatments are often nonspecific and fail to address the underlying immune signaling misregulation. This project seeks to resolve how NF-κB achieves outcome specificity utilizing Hydroides elegans, a marine annelid with an innate-only immune system and a uniquely diverse set of NF-κB homologs. In Hydroides larvae, the bacterial toxin Mif1 elicits opposite outcomes in a dose-dependent manner (low concentrations induce morphogenesis, while high concentrations cause cytotoxicity). Using a novel RNAi platform developed by the candidate, the project will integrate spatial gene expression mapping (AIM 1), functional knockdowns (AIM 2), and downstream transcriptomic profiling (AIM 3) to elucidate how distinct NF- κB homologs mediate resilience or pathology in response to the same microbial input. The overarching hypothesis is that individual NF-κB homologs function within spatially distinct cellular domains and regulate both shared and unique transcriptional programs that determine the outcome of microbial challenge. By generating a systems-level model of NF-κB immune specificity, this proposal will directly inform strategies to selectively modulate NF-κB signaling, allowing for more targeted and effective IBD therapeutics. The proposed work will also provide rigorous training in host–microbe interactions and innate immunity, positioning me for a biomedical career at the interface of translational immunology and microbiology.

Up to $41K

2028-04-30

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

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