Wednesday, February 5, 2025 2/5/2025

Regulation of spatial organization and cell-cell communication in the islet of Langerhans

Award Number: R01DK121706
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Abstract

Coordinated hormone secretion from the different endocrine cell types in the islets of Langerhans is critical to glucose homeostasis. Spatial islet organization and cell-cell communication are disrupted in obesity, insulin resistance and diabetes, leading to loss of coordinated hormone regulation. Despite the critical roles of islet organization and cell-cell communication in islet function, drugs that target them as potential therapies to diabetes have not yet been developed. Roundabout (Robo) receptors are cell adhesion proteins expressed in the islet. Robo receptors can link cell-cell contact to cytoskeleton dynamic and vesicle transport in insulin secretion. The expression Robo in the islets of mice and humans are severely diminished in obesity and diabetes. We have recently found that deletion of Robo1 and Robo2 in beta cells in mice results in loss of islet organization and impaired glucose tolerance. We further demonstrated that the islet phenotype seen upon beta cell-selective deletion of Robo is not due to transdifferentiation of beta cells to alpha or delta cells, nor is it the result of loss of beta cell maturation or beta cell death. Rather, our results led us to hypothesize that expression of Robo in beta cells facilitates correct islet organization which is required for endocrine cell-cell communication and correct glucose response. According to this hypothesis, the downregulation of Robo in obesity disrupts islet organization, leading to loss of cell-cell communication, thus contributing to dysfunctional glucose response. Understanding how expression of Robo in beta cells regulates islet organization and hormone secretion will provide the basis for new pharmacological approaches to diabetes. We will test the above hypothesis with two specific aims: in Aim 1, we will test the hypothesis that deletion of Robo in beta cells impairs insulin and glucagon secretion. We will further test the hypothesis that deletion of Robo disrupts functional beta cell-beta cell coupling using intravital visualization of synchronized insulin secretion. We will also test the hypothesis that Robo regulates hormone secretion through mediating endocrine cell-cell adhesion. In Aim 2, we will determine how expression of Robo in beta cells controls islet organization, and determine the involvement of the Robo ligand, Slit, in this process. We will further identify signaling pathways and downstream Robo targets in beta cells which could account for the defects in islet organization and glucose tolerance. These data will have important impact on diabetes in three translational aspects: 1) Robo signaling may be manipulated to prevent and restore the deterioration in islet organization and endocrine cell-cell communication in type-2 diabetics; 2) Robo signaling may be used to confer correct 3D organization and cell-cell contact in human pluripotent stem cells-derived islet-like clusters in vitro, to generate an unlimited source of bona fide islets for transplantation, and 3) Robo receptors and their extracellular ligand, Slit, may be used in bioengineering approaches for developing matrix scaffolds that could support structural integrity, survival and function in cadaver islets in clinical islet transplantation settings.


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 = $598,709 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	1/8/2025	COMPETING CONTINUATION	$0
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	11/22/2024	COMPETING CONTINUATION	$598,709
2025	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	11/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $598,709

Issue Date FY: 2023 ( Subtotal = $382,090 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/26/2023	NON-COMPETING CONTINUATION	$382,090
														Subtotal = $382,090

Issue Date FY: 2022 ( Subtotal = $382,090 )
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/1/2022	NON-COMPETING CONTINUATION	$382,090
														Subtotal = $382,090

Issue Date FY: 2021 ( Subtotal = $382,090 )
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/11/2021	NON-COMPETING CONTINUATION	$382,090
														Subtotal = $382,090

Issue Date FY: 2020 ( Subtotal = $380,900 )
2020	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/11/2020	NON-COMPETING CONTINUATION	$380,900
														Subtotal = $380,900

Issue Date FY: 2019 ( Subtotal = $380,900 )
2019	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/20/2019	NEW	$380,900
														Subtotal = $380,900

Grand Total All Awards = $2,506,779

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Regulation of spatial organization and cell-cell communication in the islet of Langerhans

Award Number: R01DK121706

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer