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Characterization of a G Protein-Coupled Receptor Implicated in Intestinal Lipid Homeostasis of Drosophila melanogaster.

Award Number: F31DK130254
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: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 04/25/2025
AWARD TERMINATION DATE: 05/01/2025

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Characterization of a G Protein-Coupled Receptor Implicated in Intestinal Lipid Homeostasis of Drosophila melanogaster. - Abstract Substantial evidence suggests that the ability to sense and respond to nutrients in the intestinal lumen can determine predisposition to metabolic disorders such as obesity and diabetes. The enteroendocrine cell (EEC) is responsible for this function despite being the least abundant cell type in the intestine. In response to intestinal stimulants, EECs synthesize and secrete enteroendocrine peptides (EEPs) that control important physiological processes including satiety, intestinal contractions, and systemic metabolism. Although EEP function has been extensively studied, the connection between EEP synthesis and secretion pathways is poorly understood. Our lab uses Drosophila melanogaster, a genetically tractable model organism, to study conserved intestinal processes. Preliminary studies in Drosophila established a link between the previously uncharacterized, EEC-specific G protein-coupled receptor GPRx and lipid homeostasis in the intestine. Specifically, GPRx mutant flies exhibit lipid droplet accumulation in their intestines despite no changes in the number of EECs expressing tachykinin (Tk), an EEP that represses lipid synthesis in Drosophila. Published studies suggest a possible connection between GPRx and calcium (Ca2+)-mediated exocytosis and further unpublished work in our lab pointed to a downstream role of the calcium response factor CaMKII. CaMKII is known to promote production and release of neurotransmitters and in related insect species, it was shown to act in response to the Drosophila steroid hormone 20-hydroxyecdysone (20E). The aim of this work is to elucidate the function of GPRx in the maintenance intestinal lipid homeostasis and assess co-regulation of Tk transcription and release. First I will test the hypothesis that GPRx modulates Tk release from EECs via Ca2+- mediated exocytosis. To do this, I will employ live imaging techniques to determine whether GPRx has an impact on calcium transients in EECs. I will also assess the ability of an exocytosis inducer to bypass GPRx and rescue the lipid accumulation phenotype observed in GPRx mutant and knockdown flies using fluorescence microscopy. Additionally, I plan to identify the factor(s) that triggers GPRx stimulation. Of particular interest are acetate and 20E because in addition to regulating Tk transcription and activation of CaMKII, respectively, both can rescue the lipid accumulation phenotype observed in antibiotic-treated flies when added to the fly diet. Thus, I will first determine whether acetate and 20E regulate GPRx expression and then, through genetic manipulation, assess the impact of acetate availability on the ability of GPRx to maintain intestinal lipid homeostasis. Lastly, I will test the role of GPRx in acetate- and 20E-mediated rescue of intestinal lipid homeostasis in antibiotic-treated flies. Collectively, experimental outcomes will 1) elucidate the role of GPRx in the maintenance of intestinal lipid homeostasis and 2) provide new insights into the regulatory connection between EEP expression and secretion. Therefore, findings could potentially inform innovative therapeutic strategies for the treatment of metabolic 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 = -$1,883 )
2026	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/25/2026	TERMINATION	-$1,883
														Subtotal = -$1,883

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/1/2025	TERMINATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $36,796 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/26/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/21/2023	NON-COMPETING CONTINUATION	$35,516
														Subtotal = $36,796

Issue Date FY: 2023 ( Subtotal = $35,516 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/23/2022	NON-COMPETING CONTINUATION	$34,574
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/10/2023	NON-COMPETING CONTINUATION	$942
														Subtotal = $35,516

Issue Date FY: 2021 ( Subtotal = $39,780 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/12/2021	NEW	$39,780
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	8/12/2021	NEW	$0
														Subtotal = $39,780

Grand Total All Awards = $110,209

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Characterization of a G Protein-Coupled Receptor Implicated in Intestinal Lipid Homeostasis of Drosophila melanogaster.

Award Number: F31DK130254

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: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 04/25/2025

AWARD TERMINATION DATE: 05/01/2025

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