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Probing the Role of Insulin-Like Growth Factor-Binding Protein 3 and Humanin in Regulating Hyaluronan Function

Award Number: R15GM131222
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Probing the Role of Insulin-Like Growth Factor-Binding Protein 3 and Humanin in Regulating Hyaluronan Function - PROJECT SUMMARY Glycosaminoglycans (GAGs), components of the highly dynamic extracellular matrix (ECM), play a crucial role in the undertaking of numerous cellular processes and a variety of human diseases result from disruption of their function. Hyaluronan (HA) is a critical component of the ECM and despite its simple primary structure, it regulates cellular responses in a highly complex manner balanced by contributions from factors that include specific signaling pathways and interactions with cell receptors or other extracellular HA binding proteins. How HA acts as a versatile macromolecule that operates via different mechanisms to regulate distinct downstream signaling and how dysregulation of HA interactions affects cell viability is largely unknown, needs to be elucidated, and currently represents a significant gap in our knowledge. Our long-term goal is to unravel the basic mechanisms by which GAGs function as extracellular molecular switches to regulate cell survival. The overall objective of this proposal is to shed light on novel mechanisms employed by HA in regulating cell signaling. Our central hypothesis is that HA is a key biomolecule that regulates extracellular phosphorylation, neurotransmitter and growth factor receptor signaling, and metabolic reprograming, and that modulation of these mechanisms ultimately affects cell function. Our rationale is that gaining sufficient knowledge of these mechanisms will offer new therapeutic opportunities. Our specific aims are to test the following hypotheses: 1) Binding of HA to IGFBP-3 blocks the protein’s ability to bind humanin which can now bind amyloid beta (Aβ) blocking its phosphorylation on Ser8 by extracellular PKA; 2) Nicotine acting via either the α7-nicotinic acetylcholine receptor or the β-adrenergic receptors activates epidermal growth factor receptor and insulin-like growth factor type 1 receptor to increase PKA activity, increasing HA levels and activation of HA-CD44 signaling, inhibiting p53, increasing the levels of heparanase in the media leading to activation of ecto-casein kinase 2, inhibiting caspase-3 and blocking apoptosis; 3) Hypoxia leads to increased HA levels activating HIF-1α and glycolysis, increasing lactate production which will then activate MMP2 decreasing Aβ40/42 toxicity (A) and MMP9 increasing sE-cad levels (B) and the BDNF/pro-BDNF ratio (C), blocking apoptosis, increasing cell survival and hypoxia-induced cisplatin resistance. This proposal is significant because better understanding of these basic mechanisms will advance our knowledge of diseases resulting from dysregulation of protein-peptide- carbohydrate signaling and innovative because it will investigate heretofore-unexamined HA functions. Expected outcomes will include unraveling HA signaling networks to develop novel therapeutics targeting specific HA- mechanisms. This R15 application will have a positive impact because it will lay the groundwork to develop better approaches to target GAG-related diseases, provide an effective vehicle for introducing undergraduate and graduate students to an authentic and extensive hands-on research training at an early stage of their education, and cultivate student confidence, resilience, appreciation, and interest in biomedical research careers.


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 = $562,500 )
2025	2025	EASTERN MICHIGAN UNIVERSITY	203 PIERCE HALL	YPSILANTI	MI	48197	WASHTENAW	USA	Biomedical Research and Research Training	000	3	9/5/2025	COMPETING CONTINUATION	$562,500
														Subtotal = $562,500

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	EASTERN MICHIGAN UNIVERSITY	203 PIERCE HALL	YPSILANTI	MI	48197	WASHTENAW	USA	Biomedical Research and Research Training	001	2	1/11/2024	COMPETING CONTINUATION	$5,461
2024	2019	EASTERN MICHIGAN UNIVERSITY	203 PIERCE HALL	YPSILANTI	MI	48197	WASHTENAW	USA	Biomedical Research and Research Training	000	1	1/11/2024	NEW	-$5,461
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $445,500 )
2022	2022	EASTERN MICHIGAN UNIVERSITY	202 WELCH HALL	YPSILANTI	MI	48197	WASHTENAW	USA	Biomedical Research and Research Training	001	2	7/20/2022	COMPETING CONTINUATION	$445,500
2022	2019	EASTERN MICHIGAN UNIVERSITY	202 WELCH HALL	YPSILANTI	MI	48197	WASHTENAW	USA	Biomedical Research and Research Training	000	1	7/12/2022	NEW	$0
														Subtotal = $445,500

Issue Date FY: 2019 ( Subtotal = $445,500 )
2019	2019	EASTERN MICHIGAN UNIVERSITY	202 WELCH HALL	YPSILANTI	MI	48197	WASHTENAW	USA	Biomedical Research and Research Training	000	1	8/6/2019	NEW	$445,500
														Subtotal = $445,500

Grand Total All Awards = $1,453,500

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Probing the Role of Insulin-Like Growth Factor-Binding Protein 3 and Humanin in Regulating Hyaluronan Function

Award Number: R15GM131222

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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