# TGF-beta Signaling Mechanisms in C. elegans Physiology and Homeostasis

> **NIH NIH R35** · QUEENS COLLEGE · 2024 · $381,000

## Abstract

Project Summary
The Transforming Growth Factor beta (TGF-β) family of secreted peptide growth factors plays significant roles
in cell function, tissue patterning, and organismal homeostasis. Dysregulation of TGF-β signaling pathways is
associated with many diseases and disorders, including cancer, cardiovascular disease, and developmental
disorders. These ligands can be divided into bone morphogenetic protein (BMP) and TGF-β/Activin subfamilies
that predominantly signal through discrete signaling pathways composed of heterotetrameric receptors and
Smad signal transducers. Many of the ligands have context-dependent and/or concentration-dependent
functions. BMPs are best known for their roles in development, but evidence is emerging for their roles as
regulators of homeostasis. While the core components of TGF-β signaling pathways have been identified for
more than 25 years, how these pathways produce context-dependent outcomes remains poorly understood. In
the nematode Caenorhabditis elegans, there are only five TGF-β ligands, two type I receptors, and one type II
receptor, providing an opportunity to dissect ligand-ligand and ligand-receptor interactions in a smaller number
of combinations than in vertebrates. Our preliminary data have established that DBL-1/BMP functions in lipid
metabolism and in innate immunity through mechanisms that are distinct from its roles in development.
Furthermore, we identified a role for TIG-2 (BMP-like) and TIG-3 (TGF-β/Activin-like) in the immune response
that may be mediated by the BMP-responsive Smad SMA-3. We are therefore poised to exploit this system to
identify context-dependent mechanisms that distinguish these physiological outcomes from the developmental
functions of signaling. Our research goals are to address these unanswered questions: (1) What are the
determinants of signaling specificity for TGF-β-related signaling pathways? Hypothesis: Alternative
ligand-ligand and ligand-receptor interactions are a mechanism for context-dependent responses. (2) How
does BMP signaling execute its fat-regulatory function at the subcellular and molecular levels?
Hypothesis: Genetic suppressors of the low-fat phenotype of dbl-1 mutants will reveal regulatory networks that
interact with BMP signaling to modulate fat storage. (3) Does altered lipid metabolism impact resilience to
pathogen exposure? Hypothesis: BMP-dependent mobilization of lipid stores contributes to survival on
pathogenic bacteria. Our established assays for fat accumulation and pathogen survival provide whole-
organism functional assessments for signaling. We will employ classical genetics, imaging, genomics, and
biochemistry to test our hypotheses at a mechanistic level. This integration of approaches, combined with the
reduced quantitative complexity in TGF-β signaling components, makes C. elegans the ideal model to address
these gaps in knowledge. Due to the high degree of conservation of TGF-β signaling pathways, we anticipate
valuable insight into...

## Key facts

- **NIH application ID:** 10841914
- **Project number:** 1R35GM153390-01
- **Recipient organization:** QUEENS COLLEGE
- **Principal Investigator:** CATHY SAVAGE-DUNN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $381,000
- **Award type:** 1
- **Project period:** 2024-04-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841914

## Citation

> US National Institutes of Health, RePORTER application 10841914, TGF-beta Signaling Mechanisms in C. elegans Physiology and Homeostasis (1R35GM153390-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10841914. Licensed CC0.

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