# Establishing the role of OCRL as a novel ciliary gene in weight regulation in human and murine models

> **NIH NIH R21** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $205,625

## Abstract

PROJECT SUMMARY
Understanding the molecular biology behind weight regulation is imperative to address the growing epidemic of
obesity and the urgent need for therapies. The primary cilium has been identified as an important organelle for
signaling and function of eukaryotic cells including the cells involved in energy homeostasis. Ciliary dysfunction
results in several human syndromes, collectively called ciliopathies, that are associated with diverse
phenotypes affecting nearly every tissue and organ system. Some ciliopathies, such as Bardet-Biedl syndrome
and Alström syndrome, present with obesity in childhood. Primary cilia are known to be expressed in the
weight regulation centers of the hypothalamus. Loss of function in these primary cilia causes disruption in the
neuroendocrine signaling pathways involved in energy homeostasis, resulting in obesity. Animal models show
that disruption of ciliary gene(s) in neurons secreting pro-opiomelanocortin, the satiety producing neuropeptide,
causes hyperphagia and obesity. The number of genes identified to be involved in the function of the primary
cilium have increased over time. Recent evidence shows that the inositol phosphatase OCRL, a gene known to
cause Oculocerebral syndrome of Lowe (LS), is expressed in the cilia, and may have a role in regulating the
levels of phosphoinositol-4-phosphate and trafficking in the cilia. OCRL is also highly expressed in the
hypothalamus, especially the cells expressing the satiety neuropeptide, pro-opiomelanocortin (POMC), and
growth hormone releasing hormone. We have identified a family of two male siblings with a previously
unknown mutation in the C-terminus of OCRL that is only expressed in the brain specific isoform. The proband
has severe obesity and other diverse clinical features, different from those seen in LS, but overlapping with
ciliopathy. We hypothesize that this loss of function variant limited to the brain-specific isoform causes a
diverse phenotype including severe obesity, but does not affect the other somatic tissues. Thus, it provides a
unique opportunity to study the brain limited impact of the loss of function of OCRL. This proposal seeks to use
this phenotype to establish the role of OCRL as a ciliary gene involved in weight regulation in human and
mouse models. We will use our patient-specific induced pluripotent stem cell line, their isogenic control and
allelic series to differentiate into arcuate-like hypothalamic neurons expressing POMC to assess the impact of
the mutation on the neuropeptide. We will also use conditional knockout of the gene by AAV-mediated RNA
interference in the arcuate and paraventricular nuclei of the brain in LS-specific humanized mouse model to
assess the phenotype. These studies will contribute a new gene to the growing list of genes involved in weight
regulation and ciliary function. It will also expand the phenotype for LS and potentially provide avenues to
explore therapies in future.

## Key facts

- **NIH application ID:** 10528081
- **Project number:** 1R21DK129893-01A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Vidhu V. Thaker
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $205,625
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10528081

## Citation

> US National Institutes of Health, RePORTER application 10528081, Establishing the role of OCRL as a novel ciliary gene in weight regulation in human and murine models (1R21DK129893-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10528081. Licensed CC0.

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