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Optimizing Peptide Inhibitors of Human Iapp Amyloidogenicity and Identifying their Effects on the Unfolded Protein Response System

Award Number: R15DK112172
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/09/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2023

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Optimizing Peptide Inhibitors of Human Iapp Amyloidogenicity and Identifying their Effects on the Unfolded Protein Response System - Project Summary/Abstract The aggregation of the 37-amino acid polypeptide human Islet Amyloid Polypeptide (hIAPP, amylin), as either insoluble amyloid or as small oligomers, appears to play a direct role in the death of pancreatic β-islet cells in type 2 diabetes. While hIAPP is the primary component of type 2 diabetes amyloid, the molecular interactions responsible for this aggregation are not well understood. hIAPP is found as extracellular deposits of amyloid in approximately 90% of patients afflicted with type 2 diabetes. hIAPP has also been shown to be a toxic agent in vitro when added to mammalian cells. While it remains unclear how self-assembly of hIAPP leads to the development of disease, recent studies have suggested that the formation of lower order protein aggregates (two to ten self- assembled proteins) leads to cellular toxicity and ultimately to the progression of disease. Preventing the formation of these toxic oligomeric species may slow, if not prevent entirely, the progression of type 2 diabetes. We have identified a series of peptides capable of inhibiting hIAPP aggregation. We propose characterizing and optimizing these peptides to yield potent hIAPP aggregation inhibitors. We will then use these inhibitors to analyze and understand the unfolded protein response system in mammalian cells. We will use a combination of rational protein engineering and molecular screening to yield optimized hIAPP aggregation inhibitors. In this screen, the gene for hIAPP is genetically fused to the gene for enhanced green fluorescent protein (EGFP). When the hIAPP-EGFP fusion protein is expressed in E. coli the natural propensity of hIAPP to aggregate precludes EGFP from folding and fluorescing. However, in the presence of peptides that prevent amyloid aggregation, the fused EGFP can fold properly and fluoresce green. Using this screen and elements of rational protein engineering, we will identify potent inhibitors of hIAPP aggregation. We will use these aggregation inhibitors, to identify the relevant genes involved in the pancreatic unfolded protein response system.


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 = -$36,819 )
2024	2019	LOYOLA MARYMOUNT UNIVERSITY	1 LMU DR	LOS ANGELES	CA	90045	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/23/2024	COMPETING CONTINUATION	-$36,819
														Subtotal = -$36,819

Issue Date FY: 2019 ( Subtotal = $407,364 )
2019	2019	LOYOLA MARYMOUNT UNIVERSITY	1 LMU DR UHALL STE 4900	LOS ANGELES	CA	90045	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	9/12/2019	COMPETING CONTINUATION	$407,364
														Subtotal = $407,364

Issue Date FY: 2016 ( Subtotal = $392,175 )
2016	2016	LOYOLA MARYMOUNT UNIVERSITY	7900 LOYOLA BLVD	LOS ANGELES	CA	90045	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/16/2016	NEW	$392,175
														Subtotal = $392,175

Grand Total All Awards = $762,720

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Optimizing Peptide Inhibitors of Human Iapp Amyloidogenicity and Identifying their Effects on the Unfolded Protein Response System

Award Number: R15DK112172

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/09/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2023

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