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Investigating the structure and function of GPRC5B in a rare leukoencephalopathy

Award Number: R03NS148823
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/03/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Investigating the structure and function of GPRC5B in a rare leukoencephalopathy - Project Summary G protein-coupled receptors (GPCRs) for hormones and neurotransmitters evolved to be one of the most important means of communication between cells and tissues in higher organisms. They are responsive to a wide range of stimuli, from light to small molecules and proteins. As a result of their extensive influence over human physiology and behavior, more than 30% of FDA-approved drugs target GPCRs. Yet, over half of the non-olfactory GPCRs (around 165) have not been therapeutically targeted. One such GPCR, GPRC5B, is a family C orphan GPCR that has been shown to have a critical function for lymphatic development, regulation of inflammatory responses, and controlling vascular tone. Murine models have demonstrated that knock-out of GPRC5B in smooth muscle cells is highly protective against the development of atherosclerotic plaques, suggesting that GPRC5B could be a new target for treating atherosclerosis, which affects over 18 million Americans. However, GPRC5B’s role in the rare disease Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC) is perhaps most acutely striking. MLC is a debilitating neurological condition where a lack of volume regulation in astrocytes results in chronic white matter edema. Most commonly, MLC is caused by mutations in the MLC1 protein. However, some patients with no mutations in MLC1 were found to have heterozygous missense mutations in GPRC5B. These patients showed a particularly severe MLC phenotype. Patients with these GPRC5B mutations have dramatically increased levels of GPRC5B protein, which in models is sufficient to disrupt normal volume homeostasis. How these mutations alter GPRC5B function is unknown, and no treatment is available for MLC. This work will investigate GPRC5B to understand its (mis)function in MLC. To enable our studies, we will use alpaca-derived antibodies, called nanobodies (Nbs), which bind antigens exclusively via the variable domain of their heavy chain. These small protein tools will facilitate the determination of the molecular structure of GPRC5B by cryo-EM. We will also use single-molecule fluorescence strategies together with molecular dynamics simulations to investigate molecular movements within GPRC5B to understand its native functions as well as the effect of MLC mutations. We believe that through this pilot project, we will gain valuable insights into the biology of this poorly characterized GPCR and how mutations in GPRC5B may influence cellular volume control mechanisms, as those that lead to MLC. Lastly, while our goal is for the tools and structural insights that result from this work to enable us to target GPRC5B for treating MLC, there is a potential for targeting GPRC5B in other diseases such as cancer and cardiovascular disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $156,000 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/3/2026	NEW	$156,000
														Subtotal = $156,000

Grand Total All Awards = $156,000

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Investigating the structure and function of GPRC5B in a rare leukoencephalopathy

Award Number: R03NS148823

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/03/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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