Implications of changes in islet exosomal cargo in type 1 diabetes

Active Project Grant Awarded Last action

Award ID
R01DK133881
Recipient
Awarding agency
Obligated
$4,771,505

Award facts

Completion date 84% complete
Originally
Place of performance
Indianapolis, IN 46202, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Extracellular vesicles (EVS) are membrane bound nanoparticles that can interact with other cells as a means of cell:cell communication. Emerging data suggest that SS cell-derived exosomes, an EV subtype released by exocytosis of multivesicular bodies, may act as paracrine effectors in islet health. Given the potential for exosomes to play a role in SS cell communication with surrounding cells in the islet microenvironment, a critical need exists for deliberate research defining mechanisms of SS cell exosome biology under physiologic and pathophysiologic circumstances. SS cell expression of the transmembrane immune checkpoint protein death-ligand 1 (PD-L1) plays a key role to support SS cell survival in type 1 diabetes (T1D). Preliminary data suggest that SS cell exosome membranes carry PD-L1, and that exosomal PD-L1 is upregulated by cytokine treatment of parent SS cells. Our central hypothesis is that stressed SS cells in the T1D microenvironment alter their exosomal contents to include protective mechanisms aimed at evading SS cell destruction associated with autoimmunity. Aim 1 will elucidate the mechanistic etiology of altered SS cell exosome PD-L1 cargo. We hypothesize that proinflammatory interferon signaling activates molecular regulators of intracellular SS cell PD-L1 that, in concert with mediators of exosome biogenesis, increase total exosomal PD-L1. Chemical and genetic manipulation will be used to test impacts of these pathways on SS cell exosomal PD-L1. Aim 2 will test the hypothesis that via transfer to or interaction with surrounding SS cells and t cells, SS cell exosomal PD-L1 loading is a protective mechanism shielding SS cells from autoimmune destruction. Use of SS cells differentiated from a human induced pluripotent stem cell line overexpressing GFP-tagged PD-L1 will allow for direct tracking of PD-L1 transfer and binding to other SS cells and CD8+ t cells. Aim 3 will employ a novel microfluidic device to test the hypothesis that PD-L1+ exosome release will be increased in humans with or at risk for T1D. We will quantify differences in total and islet-derived EV PD-L1 in human plasma or pancreas slice media and compare to nondiabetic controls. Testing will also be performed in plasma from individuals with longstanding T1D with or without residual detectable c-peptide to determine if plasma islet-derived EV PD-L1 is linked to functional SS cell survival. This work will lead to a paradigm shift in the field's understanding of SS cell communication with surrounding cells, and determine the clinical potential of islet-derived PD-L1 exosome cargo as a therapeutic targeting SS cell survival or a biomarker to dissect T1D disease-related heterogeneity.

Transactions

Action Obligated Date
Amendment $0
Amendment $0
Amendment $0
Amendment $653,342
Amendment $653,342
Amendment $664,681
Amendment $684,254
Amendment $684,254
Amendment $715,816
Original award $715,816

Subawards

Subrecipient Amount Awarded
The University Of Chicago The Mirmira lab will perform assays from human islets and from human EndoC 􀈕 cells focusing on isolating and analyzing exosomes and microvesicles. The Mirmira… $282,086
Battelle Memorial Institute Type 1 diabetes (T1D) results from the pancreatic beta-cell death by an autoimmune inflammatory response. Communication between neighboring beta cells and… $107,310
Universite Libre De Bruxelles STATEMENT OF WORK Universite Libre de Bruxelles For the proposal titled “Implications of Changes in Islet Exosomal Cargo in Type 1 Diabetes� the… $65,019
Regenstrief Institute Inc. Dr. Michael Bushey will lead all activities to be performed at the Indiana University Health (IUH) site and will be responsible for the conduct and oversight of… $431,176
Purdue University In this research, we propose to use microfluidic-based technologies for islet-derived exosome separation and detection. Microfluidic techniques have shown… $92,072

Quick answers

Who received award R01DK133881?

R01DK133881 was awarded to Trustees Of Indiana University by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on September 19, 2022.

How much is award R01DK133881 worth?

$4,771,505 has been obligated on R01DK133881.

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