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Improved Targeting of Somatostatin Receptors for Pediatric Conditions

Award Number: K99HD107581
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 01/12/2024

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Improved Targeting of Somatostatin Receptors for Pediatric Conditions - PROJECT ABSTRACT Improved Targeting of Somatostatin Receptors for Pediatric Conditions Gigantism is a childhood developmental disorder whereby abnormally high levels of growth hormone result in excessive growth in both height and girth. The disorder can have serious physical complications including diabetes and loss of vision as well as social isolation. In the majority of cases gigantism is caused by pituitary adenomas which, when surgery is not an option, is treated with somatostatin receptor agonists to suppress growth hormone levels and provide symptom relief. Somatostatin receptors (SSTRs) are G protein coupled receptors (GPCRs) highly expressed in pituitary adenomas. Two analogues of the endogenous peptide, octreotide and lanreotide, were originally developed as SSTR2-selective, long-lasting peptide therapeutics for gigantism and other conditions. While they have proved successful, long-term side effects and other suboptimal properties drive the need for improved pharmaceutical interventions for gigantism. Much remains unknown about SSTRs and their pharmacology. To date, I have determined structures of SSTR2, however some questions of subtype selectivity remain unanswered without structures of the other subtypes. Much of the additional information about SSTR signaling partners is based upon downstream cellular assays, and much remains unknown about the relevance of SSTR subtype selectivity and signaling partner bias. Here I propose to utilize a combination of structural characterization with cryogenic electron microscopy (cryoEM), molecular dynamics simulations, and biochemical assays in order to characterize the selectivity, activation, and signaling profiles of SSTRs. The work will build upon my existing skillset in molecular simulations, modelling, and protein biochemistry while providing invaluable training in cryoEM data collection/processing and cell-based biochemical assays. Successful completion of this work will provide critical insight into the signaling landscape of the somatostatin receptor and the structural basis for both ligand-based and SSTR-subtype-based G protein selectivity. This will bridge several gaps in knowledge of SSTRs that should help in the development of improved, small molecule therapeutics that do not require repeated injections in children.


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: 2024 ( Subtotal = -$86,950 )
2024	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	001	2	7/16/2024	NON-COMPETING CONTINUATION	$0
2024	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	002	2	8/14/2024	NON-COMPETING CONTINUATION	-$86,950
2024	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	000	2	4/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = -$86,950

Issue Date FY: 2023 ( Subtotal = $121,999 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	000	2	8/10/2023	NON-COMPETING CONTINUATION	$121,999
														Subtotal = $121,999

Issue Date FY: 2022 ( Subtotal = $121,999 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	000	1	8/21/2022	NEW	$121,999
														Subtotal = $121,999

Grand Total All Awards = $157,048

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Improved Targeting of Somatostatin Receptors for Pediatric Conditions

Award Number: K99HD107581

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 01/12/2024

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