# Ciliary trafficking mechanisms underlying the human genetics of obesity

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $489,195

## Abstract

PROJECT SUMMARY
Primary cilia are signaling centers directing sensory signaling in diverse tissues including the brain. Human
ciliopathies including Bardet-Biedl syndrome present with a range of deficiencies including retinal
degeneration, renal disease, and hyperphagia-driven hypothalamic obesity. Using tandem affinity purification
of ciliopathy gene products, the lab has identified key regulators and effectors of these disease genes.
Specifically, identification of the BBSome, a complex in central to Bardet-Biedl syndrome provided key insights
into the trafficking of GPCRs into cilia. Extending the strategy to look systematically at proteins interacting with
the gene products of monogenic obesity syndromes, the Tubby obesity protein was found copurifying with the
intraflagellar A complex. Both BBS and Tubby/Tulp3 are important regulators of GPCR trafficking into primary
cilia, providing important criteria to identify bona fide ciliary receptors. Using these criteria, the neuropeptide Y
family of GPCRs, notably NPY2R, were discovered to be an important determinant of Bardet-Biedl syndrome.
This proposal is focused on the newly identified monogenic obesity gene Cep19, which is recruited by
FGFR1OP/FOP, CEP350 and a new ciliary GTPase and a candidate obesity gene, Rabl2B. Work here led to
the discovery that the IFT-B complex is the central effector of Rabl2B and that Rabl2B is required for IFT-B to
assemble cilia. By defining mechanisms regulating the Rabl2B GTPase mechanism, including the
identification of GEF and GAP, a critical goal is to understand how the entry of IFT-B into cilia is regulated and
how misregulation causes defects in ciliary trafficking of obesity regulators. Additional studies will focus on the
ciliary anchors for the Cep19-Rabl2B pathway on the ciliary distal appendage, a set of two pilot studies to look
at interactions from two other monogenic obesity genes, adenylate cyclase 3 and Ncs1, and finally to look
these trafficking mechanisms controlling GPCR trafficking, the effects of these pathways in Rabl2 knockout
mice, and to look for additional human patient lesions in newly identified candidate obesity genes.

## Key facts

- **NIH application ID:** 9980198
- **Project number:** 5R01GM121565-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** PETER Kent JACKSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $489,195
- **Award type:** 5
- **Project period:** 2017-03-01 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980198

## Citation

> US National Institutes of Health, RePORTER application 9980198, Ciliary trafficking mechanisms underlying the human genetics of obesity (5R01GM121565-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9980198. Licensed CC0.

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