Research

Summary

Our lab studies inter-organ communication via proteins in blood circulation (e.g. hormones). We are interested in answering long-standing questions such as:

· Where do circulating proteins come from and where do they go? (i.e. cell-types)

· Which proteins mediate inter-organ communication?

· What is the binding specificity of inter-organ molecules? (e.g. hormones)

By mapping protein networks between organs, discovering novel circulating factors, and applying new approaches to well-studied hormones, we aim to understand basic mechanisms of inter-organ communication, improve disease diagnosis, and identify therapeutic targets and biomarkers for human diseases.

We use a combination of experimental and computational tools, including protein proximity labeling (e.g. TurboID) to map the origins and destinations of blood proteins, mass spectrometry of blood plasma, in-silico biomolecular interaction screens (e.g. AlphaFold), and genome engineering tools (e.g. CRISPR) to visualize and perturb candidate inter-organ factors. For in-vivo experiments, we use Drosophila, a model animal with human-like organ systems and precise tissue-specific genetic tools.

Inter-organ mapping

Circulating hormones that bind receptors play key roles in inter-organ communication, but their discovery using traditional experimental approaches has been slow and incremental. Recent advances in proximity labeling enzymes and AI-driven protein structure modeling now enable large-scale unbiased mapping of inter-organ communication. Our lab is adapting these new tools and developing our own to study inter-organ communication.

Proximity labeling enzymes are powerful tools to map the origins and destinations of secreted proteins in vivo. During Dr. Bosch’s postdoc, he showed that TurboID is an effective proximity labeling tool in live Drosophila tissues (Branon et al. 2019, Droujinine et al. 2021). More recently, he applied TurboID to identify the origins of secreted proteins from 10 major tissue types, revealing an unprecedented tissue-secretome map of proteins in circulation (Bosch et al. 2025), and candidate inter-organ factors (below). Our lab is adapting this tissue-secretome mapping technique to disease models to identify tissue-specific induced factors that promote or prevent disease pathology. We are also developing new proximity labeling approaches to map and discover inter-organ proteins, such as tissue “receive-ome” tools that complement our existing tissue secretome approach.

Recent advances in AI models now enable in-silico prediction of biomolecular interactions (PPIs), facilitating large-scale, high-throughput screens for novel hormone-receptor pairs. Unfortunately, these in-silico screens are computationally prohibitive. Our lab developed an efficient computational pipeline using GPUs at the University of Utah Center for High Performance Computing (CHPC), which dramatically reduces computation time, expense, and manual intervention. Our lab is screening hundreds of thousands of Drosophila hormone-receptor pairs and have uncovered interesting candidates (see below). This unbiased in-silico screen provides new steps toward an unprecedented systems-level view of inter-organ communication that complements our proximity labeling approaches. We are also working to make our in-silico interaction screens more efficient and take advantage of ever improving software tools.

We are looking for new members with experimental or computational experience to spearhead these high-risk high-reward discovery projects. These projects are most suitable for post-docs.

Studying novel inter-organ factors

Many candidate inter-organ factors came out of our inter-organ ‘omics’ screens (above), and current projects in the lab involve characterizing these factors in Drosophila. For example, we are studying two secreted factors that independently regulate body size, implying systemic roles. In addition, we are studying a circulating protein that we believe targets neuronal synapses and regulates synaptic strength. Current and future screens will continue to generate new inter-organ factors for molecular characterization.

We are recruiting new members to take ownership over an inter-organ factor, and in some cases have the privilege to give them a name. These projects are most suitable for graduate students as they have a clear roadmap toward a publication.

Genetic tool development

Characterizing inter-organ factors in vivo requires a panel of genetic reagents (i.e. transgenic flies) including gene knock-out, knock-in, overexpression, RNAi, and protein tagging. In Dr. Bosch’s post-doc, he developed CRISPR/Cas9 methods to generate these reagents faster (Bosch et al. 2020, Bosch et al. 2021, Bosch et al. 2022, Bosch et al. 2023, Zirin et al. 2024). Our lab employs several plasmid cloning and transgenic pipelines and adapts and develops new gene editing tools for Drosophila, such as improved methods to make DNA base changes or insert large DNA.

In addition to genome editing tools, we are always exploring new genetic methods in Drosophila and beyond. For example, we are developing a modular plasmid cloning system to express multiple ORFs as a polycistronic transcript in any organism, as well as a genetically encoded auto-bioluminescence reporter in animals (i.e. glowing flies).

We are looking for graduate students and post-docs members that will pursue genetic tool-focused projects as a side project to complement their primary biological project, or for an undergraduate main project.

Hormone-receptor binding specificity

Hormones “signal” by binding receptor proteins, but the molecular rules of binding specificity is not fully understood. For example, pathogenic missense variants can disrupt hormone-receptor binding, but we currently can’t yet predict all missense variants that disrupt binding. Furthermore, it’s possible that non-canonical “crosstalk” binding between hormones and receptors has been overlooked. Our lab is using in-silico binding approaches (e.g. AlphaFold) to map and discover hormone-receptor binding specificity and validate our predictions in cell and animal models. We expect broad impact, including deeper insight into hormone-receptor biology and improving the interpretation of missense variants in patient genomes.

For example, we are modeling the effects of missense mutations on hormones-receptor binding specificity. Pilot efforts of saturation mutagenesis of the Insulin-Insulin Receptor (Ins-InsR) identified missense mutations that are predicted to disrupt binding and are known to be pathogenic in humans. We are also systematically testing and exploring the landscape of alternative hormone-receptor binding (aka crosstalk signaling). By screening thousands of possible pairs, we identified several non-canonical human hormone-receptor pairs for follow-up.

We are currently focusing these efforts on human hormone-receptors and anticipate results from this project will feedback into Drosophila projects to study basic mechanisms.

We are looking for a post-doc and/or graduate student to pursue this project. Particularly with a background in structural biology and/or medical genetics. Perhaps most appropriate for a MD-PhD student.

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