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Molecular mechanisms of photoreceptor outer segment morphogenesis

Award Number: R01EY012859
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/07/2000
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Molecular mechanisms of photoreceptor outer segment morphogenesis - This proposal addresses one of the most fundamental unsolved problems in vision: the molecular and cellular mechanism responsible for building and maintaining the light-sensitive organelle of vertebrate photoreceptor cells, the outer segment. The outer segment is a ciliary structure filled with a stack of disc membranes, which provide vast surfaces for light capture and harbor proteins comprising the phototransduction machinery. Discs are renewed on a daily basis in order to counteract the adverse effects of light exposure, and the fidelity of disc renewal is critical for maintaining photoreceptor health and normal vision. Previous studies established that photoreceptor discs are formed as serial evaginations of the plasma membrane at the outer segment base. Yet, the molecular mechanisms responsible for performing these membrane transformations remain poorly understood. The research strategy outlined in this proposal is built upon the recently uncovered analogy between disc formation in photoreceptor cells and a fundamental property of many other cilia types - the ability to release small extraciliary vesicles, called ectosomes. The photoreceptor cilium also has an innate ability to release massive amounts of ectosomes. However, in normal photoreceptors this process is suppressed by the disc-specific protein, peripherin-2, which retains the budding membranes at the outer segment base, thereby enabling them to be morphed into discs. The formation of both ciliary ectosomes and photoreceptor discs requires the action of the actin cytoskeleton, and recent evidence suggests that ectosome release also relies on the ESCRT protein complex. Therefore, Aim 1 will explore whether a similar interplay between the actin cytoskeleton and ESCRT proteins is responsible for performing the first steps of photoreceptor disc formation. Aim 2 will explore the mechanism by which peripherin-2 transforms the functional state of the photoreceptor cilium from releasing ectosomes to retaining membranes at the outer segment base and transforming them into discs. Elucidating these mechanisms is critical for advancing our understanding of basic photoreceptor cell biology and pathobiological mechanisms underlying photoreceptor degeneration frequently associated with defects in outer segment morphogenesis.


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 = $0 )
2024	2022	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Vision Research	000	24	2/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $430,862 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	24	5/27/2022	NON-COMPETING CONTINUATION	$430,862
														Subtotal = $430,862

Issue Date FY: 2021 ( Subtotal = $430,862 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Vision Research	001	23	5/26/2021	NON-COMPETING CONTINUATION	$430,862
2021	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	20	11/13/2020	COMPETING CONTINUATION	$0
														Subtotal = $430,862

Issue Date FY: 2020 ( Subtotal = $444,188 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	22	5/26/2020	NON-COMPETING CONTINUATION	$444,188
														Subtotal = $444,188

Issue Date FY: 2019 ( Subtotal = $443,958 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Vision Research	001	21	5/24/2019	NON-COMPETING CONTINUATION	$443,958
2019	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	19	2/6/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $443,958

Issue Date FY: 2018 ( Subtotal = $441,645 )
2018	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	20	8/8/2018	COMPETING CONTINUATION	$441,645
														Subtotal = $441,645

Issue Date FY: 2017 ( Subtotal = $391,560 )
2017	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	19	7/24/2017	NON-COMPETING CONTINUATION	$391,560
														Subtotal = $391,560

Issue Date FY: 2016 ( Subtotal = $391,677 )
2016	2016	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	18	7/4/2016	NON-COMPETING CONTINUATION	$391,677
														Subtotal = $391,677

Issue Date FY: 2015 ( Subtotal = $383,955 )
2015	2015	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	17	7/8/2015	NON-COMPETING CONTINUATION	$383,955
														Subtotal = $383,955

Issue Date FY: 2014 ( Subtotal = $387,493 )
2014	2014	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	001	16	7/14/2014	COMPETING CONTINUATION	$387,493
2014	2013	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	15	7/9/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $387,493

Issue Date FY: 2013 ( Subtotal = $511,912 )
2013	2013	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	001	15	5/29/2013	NON-COMPETING CONTINUATION	$26,942
2013	2013	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	15	1/25/2013	NON-COMPETING CONTINUATION	$484,970
														Subtotal = $511,912

Issue Date FY: 2012 ( Subtotal = $538,855 )
2012	2012	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	14	2/8/2012	NON-COMPETING CONTINUATION	$538,855
														Subtotal = $538,855

Issue Date FY: 2011 ( Subtotal = $538,855 )
2011	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	001	13	6/23/2011	NON-COMPETING CONTINUATION	$33,677
2011	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	13	2/3/2011	NON-COMPETING CONTINUATION	$505,178
														Subtotal = $538,855

Issue Date FY: 2010 ( Subtotal = $549,577 )
2010	2010	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	12	1/8/2010	COMPETING CONTINUATION	$549,577
														Subtotal = $549,577

Issue Date FY: 2009 ( Subtotal = $538,670 )
2009	2009	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	001	11	4/29/2009	NON-COMPETING CONTINUATION	$53,867
2009	2009	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	11	1/12/2009	NON-COMPETING CONTINUATION	$484,803
														Subtotal = $538,670

Issue Date FY: 2008 ( Subtotal = $512,523 )
2008	2008	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	10	3/6/2008	NON-COMPETING CONTINUATION	$512,523
														Subtotal = $512,523

Issue Date FY: 2007 ( Subtotal = $507,749 )
2007	2007	DUKE UNIVERSITY	BOX 104135	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	9	1/31/2007	NON-COMPETING CONTINUATION	$507,749
														Subtotal = $507,749

Issue Date FY: 2006 ( Subtotal = $495,735 )
2006	2006	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Vision Research	000	8	2/2/2006	NON-COMPETING CONTINUATION	$495,735
														Subtotal = $495,735

Issue Date FY: 2005 ( Subtotal = $491,279 )
2005	2005	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	6	1/31/2005	COMPETING CONTINUATION	$229,848
2005	2005	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Vision Research	000	7	7/4/2005	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$261,431
														Subtotal = $491,279

Issue Date FY: 2004 ( Subtotal = $336,962 )
2004	2004	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	5	1/12/2004	NON-COMPETING CONTINUATION	$336,962
														Subtotal = $336,962

Issue Date FY: 2003 ( Subtotal = $327,145 )
2003	2003	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	4		NON-COMPETING CONTINUATION	$327,145
														Subtotal = $327,145

Issue Date FY: 2002 ( Subtotal = $317,615 ) (Continued on the next page)
Grand Total All Awards = $10,033,257

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Molecular mechanisms of photoreceptor outer segment morphogenesis

Award Number: R01EY012859

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/07/2000

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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