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Mechanisms of structural plasticity, client interactions, and co-aggregation of the lens ⍺-crystallins

Award Number: F31EY033226
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Mechanisms of structural plasticity, client interactions, and co-aggregation of the lens ⍺-crystallins - Project Summary The ⍺-crystallins (⍺A- and ⍺B- isoforms) are essential for the development and lifelong transparency of the eye lens. As molecular chaperones – members of the small heat shock protein family – the ⍺-crystallins play an integral part of the stability of lens proteostasis and preventing the formation of age-related opacities (i.e., protein aggregates) responsible for cataract formation. However, this system may become destabilized and/or overwhelmed as a result of the long-lived nature of lens proteins, and ultimately contribute to disease progression. Despite these fundamental roles in lens transparency and disease, there remains a critical gap in our understanding of the molecular mechanisms by which the ⍺-crystallins function, and how these proteins aggregate in response to aberrant (or age-related) conditions in the lens. A hallmark feature of the ⍺-crystallins is a remarkable degree of structural plasticity that is driven by sub-domain interactions involving flexible N- and C-termini, a feature that is thought to prevent crystallization under the highly concentrated environment of the eye lens. This molecular plasticity also contributes to ⍺-crystallin chaperone function, allowing it to adapt to and sequester a diverse range of destabilized proteins (aka clients) and prevent cytotoxic aggregation. However, these same features of intrinsic dynamics have stymied previous efforts to obtain the detailed structural characterizations (atomistic details) required to provide mechanistic insights into the function of these critical components of the eye lens. The aims of this proposal will leverage recent advances in the state-of-the-art methods of single particle CryoEM cryo-electron tomography (CryoET) – coupled with biophysical and functional studies – in order to obtain high-resolution structural information regarding the mechanism of ⍺-crystallin structural plasticity/polydispersity (Aim 1). Additional insights into the pathway(s) of chaperone/client co- aggregation (Aim 2) will be garnered from NSEM, light scattering, and crosslinking-MS/MS methods. Success of these aims will fill critical gaps in knowledge that have evaded the field for decades and provide detailed mechanistic insights into the molecular basis of ⍺-crystallin’s hallmark of structural plasticity and how the lens chaperone system becomes overwhelmed leading to cytotoxic protein aggregates such as those found in cataract.


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 = -$31,340 )
2025	2022	PORTLAND STATE UNIVERSITY	1600 SW 4TH AVE	PORTLAND	OR	97201	MULTNOMAH	USA	Vision Research	000	1	1/23/2025	NEW	-$31,340
														Subtotal = -$31,340

Issue Date FY: 2024 ( Subtotal = $40,805 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	3	8/9/2024	NON-COMPETING CONTINUATION	$40,805
														Subtotal = $40,805

Issue Date FY: 2023 ( Subtotal = $39,525 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	001	2	8/25/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$39,525
2023	2022	PORTLAND STATE UNIVERSITY	1600 SW 4TH AVE	PORTLAND	OR	97201	MULTNOMAH	USA	Vision Research	000	1	8/24/2023	NEW	$0
														Subtotal = $39,525

Issue Date FY: 2022 ( Subtotal = $39,403 )
2022	2022	PORTLAND STATE UNIVERSITY	1600 SW 4TH AVE	PORTLAND	OR	97201	MULTNOMAH	USA	Vision Research	000	1	8/1/2022	NEW	$39,403
2022	2022	PORTLAND STATE UNIVERSITY	1600 SW 4TH AVE	PORTLAND	OR	97201	MULTNOMAH	USA	Vision Research	001	1	8/1/2022	NEW	$0
														Subtotal = $39,403

Grand Total All Awards = $88,393

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Mechanisms of structural plasticity, client interactions, and co-aggregation of the lens ⍺-crystallins

Award Number: F31EY033226

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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