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Development of innovative genetically encoded tools to dissect melanocortin-4 receptor signaling in neuronal circuits

Award Number: F31DK145227
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/15/2025
PERIOD OF PERFORMANCE END DATE: 07/14/2027

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Development of innovative genetically encoded tools to dissect melanocortin-4 receptor signaling in neuronal circuits - PROJECT SUMMARY/ABSTRACT The absence of genetically encoded tools capable of activating endogenous melanocortin-4 receptor (MC4R) in the brain with cell selectivity and temporal control has created a critical gap in the ability to study the neural circuits regulating feeding behavior and energy homeostasis. The long-term goal of this project is to map the melanocortin system microcircuitry by activating MC4R in specific neuronal populations to study effects on feeding behavior and physiology. Pharmacological methods lack cell-type specificity and spatial resolution, while existing chemogenetic and optogenetic techniques do not replicate natural MC4R signaling events. The overall objective of this application is to engineer genetically encoded tools capable of achieving high spatiotemporal control over MC4R activation. The rationale for this project is that surface-tethered protein switches can be employed to control the activity of the MC4R agonist alpha-melanocyte stimulating hormone (Į-MSH). Specific Aim 1 will engineer a chemogenetic controlled Į-MSH (ccMSH) for drug-dependent activation of MC4R using chemically activated protein domains (CAPs) to cage Į-MSH. The ccMSH will be optimized for high drug dependence and assessed in mammalian cell cultures to validate the system's functionality. It will then be applied to mouse models to observe behavioral and physiological responses to chemical-dependent MC4R activation. Specific Aim 2 will develop optogenetically controlled Į-MSH (ocMSH) for light-dependent activation of MC4R using the light-oxygen-voltage sensing (LOV) domain to cage Į-MSH. Directed evolution will be used to improve the membrane trafficking and photoactivation of the LOV domain. The effectiveness of ocMSH will be characterized in cell cultures and tested in mouse models to assess the impact of light-gated MC4R activation on behavior and physiology. Upon successful completion, this project will introduce innovative and novel chemogenetic and optogenetic tools that will enable detailed studies of the melanocortin system in vivo, providing high spatiotemporal resolution of endogenous MC4R activation. The anticipated outcomes will significantly impact our understanding of the regulation of energy homeostasis and feeding behavior, contributing significantly to the development of therapeutic strategies for treating obesity and related metabolic disorders.


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: 2025 ( Subtotal = $43,376 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/8/2025	NEW	$43,376
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	7/8/2025	NEW	$0
														Subtotal = $43,376

Grand Total All Awards = $43,376

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Development of innovative genetically encoded tools to dissect melanocortin-4 receptor signaling in neuronal circuits

Award Number: F31DK145227

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/15/2025

PERIOD OF PERFORMANCE END DATE: 07/14/2027

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