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Role of EphA1/A2 domain-domain and -membrane interactions for receptor specificity and Blood Brain Barrier dysfunction

Award Number: R01AG089561
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Role of EphA1/A2 domain-domain and -membrane interactions for receptor specificity and Blood Brain Barrier dysfunction - Ligand activation of Eph receptors plays a decisive role in cell migration during blood vessel formation and neuronal axon guidance. Eph receptors can also signal independently of ligands, whereby the migration- and adhesion-repulsive signaling shifts to a pro-migratory stimulus that contributes to metastasis and drug resistance in various cancers. Recent studies have substantiated the role of Eph receptors in the dysfunction of the blood brain barrier (BBB) during ischemic stroke, invasion of pathogenic organisms and the early stages of Alzheimer’s Disease (AD) and other neurodegenerative diseases. Yet, the molecular mechanisms behind Eph receptor function remain poorly understood. Eph signaling depends on a variety of inter-molecular and intra-molecular Eph-Eph interactions which involve portions of the protein structure (domains) but also the cellular membrane. The overall project seeks to identify key residues in sets of interactions, which are not yet well characterized, but are likely to be key to the different functional states of the overall protein interactions. Ephs are unique within the superfamily of transmembrane receptor tyrosine kinases due to their C-terminal 5- helix folded domain, part of the SAM (sterile alpha motif) adaptor protein family. We and others’ have reported a novel role of the SAM domain to auto-inhibit EphA2 kinase activity. In preliminary experiments for this proposal, we discovered that mutations in the SAM domain functionally mimic its complete deletion and can abolish EphA2 autoinhibition. However, the molecular details of how the SAM domain inhibits the kinase domain are still missing and will be investigated in Aim 1. EphA2 is cleaved at the cell surface by Membrane- type I matrix metalloproteinase and γ-secretase, key proteins for AD. However, the structure and function of these intracellular and extracellular-transmembrane receptor cleavage products are poorly understood. We will characterize a protein construct encompassing the intracellular region (ICR), which consists of the JM region, the Kinase Domain (KD) and the SAM domain and another with the two membrane- proximal extracellular FibroNectin III domains (FN1&2), the transmembrane (TM), the juxtamembrane (JM) region. In aim 2, we will use these EphA2 fragments to investigate the interaction between Eph domains and with the membrane. This knowledge is crucial for understanding the hierarchical organization of these regulatory interactions. The studies will be extended to the EphA1, EphA4 and EphB2 receptors, delineating how specific differences in domain-domain contacts relate to different levels of kinase activity between the different Ephs. In addition, the proximity of the Eph receptor Fibronectin domains to the membrane is noteworthy: Our preliminary data for Aim 3 support the interaction between these domains and Aβ, a key peptide in AD. The structural insights we pursue are essential for the development of diagnostic and therapeutic agents targeting neuronal and vascular diseases, including the breakdown of the blood brain barrier in neurodegenerative diseases.


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: 2026 ( Subtotal = $805,356 )
2026	2026	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	000	3	7/9/2026	NON-COMPETING CONTINUATION	$805,356
														Subtotal = $805,356

Issue Date FY: 2025 ( Subtotal = $789,248 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	000	2	7/10/2025	NON-COMPETING CONTINUATION	$789,248
														Subtotal = $789,248

Issue Date FY: 2024 ( Subtotal = $852,309 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	000	1	8/29/2024	NEW	$852,309
														Subtotal = $852,309

Grand Total All Awards = $2,446,913

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Role of EphA1/A2 domain-domain and -membrane interactions for receptor specificity and Blood Brain Barrier dysfunction

Award Number: R01AG089561

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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