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Herpes simplex virus egress from neurons into axons mediated by HSV membrane proteins gE/gI and US9 and axonal transport by kinesin motors.

Award Number: R01EY018755
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Herpes simplex virus (HSV) 1 and 2 are common a-herpesviruses that establish lifelong latency. While most HSV infections of mucosal tissues are relatively benign, there are rare cases of encephalitis and HSV infections of the cornea can produce inflammatory pathology known as herpes stromal keratitis (HSK). HSK frequently involves recurring infections, often over years, produced by virus that reactivates in sensory ganglia that then travels to the cornea, producing scarring which can eventually lead to blindness. In the U.S. there are 60,000 cases of HSK/annually and HSV remains the leading infectious cause of blindness. Recurrent HSV infections in mucosa and the eye stem from reactivation of latent virus in neurons followed by anterograde transport in neuronal axons, a process by which virus particles hitchhike on kinesin motors that ferry virus from neuron cell bodies to axon tips. Our research will study two stages of anterograde transport. The first stage involves assembly of virus particles in the cytoplasm, followed by staging or sorting of these virus particles for transport into neuronal axons. The second stage involves transport of virus particles by kinesin motors along microtubules within axons. Our studies of first stage of this process will focus on two HSV membrane proteins gE/gI and US9 that cooperate to promote the assembly of virus particles and the polarized sorting of particles into axons. We recently demonstrated that HSV gE-/US9- double mutants were unable to assemble enveloped virus particles and, instead, viral capsids accumulated on cytoplasm membranes. There was also evidence that gE/gI and US9 participate in a subsequent process, involving sorting of enveloped virions into axons. These observations represent a novel example of neuron-specific defects in virus assembly and sorting in neurons and represent a new paradigm for how gE/gI and US9 function in neurons. The research in Aim 1 will test two hypotheses: i) gE/gI and US9 promote virus assembly by collecting other viral assembly proteins on cytoplasmic membranes that are sites of virus envelopment and ii) following envelopment, gE/gI and US9 trafficking sequences promote sorting of virus particles into axons. The molecular mechanisms involved in gE/gI- and US9-mediated assembly and sorting will be investigated using novel high resolution imaging techniques coupled with a panel of viral mutants and biochemical assays. In Aim 2, we will study the second stage of anterograde transport addressing two fundamentally important questions: i) which of the many kinesin motors transport HSV particles in axons and ii) which viral proteins tether onto kinesins? To address these questions, we will take advantage of recent advances in our ability to transduce neurons using baculoviruses to deliver fluorescent cargo molecules and kinesins, “split kinesins” and miRNAs to silence kinesins allowing us to determine which kinesins are functionally important for HSV anterograde transport. Based on our recent identification of certain kinesins that transport HSV, we now have the opportunity to identify HSV proteins that tether onto these kinesin motors.


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	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	23	3/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $446,960 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	23	3/13/2023	NON-COMPETING CONTINUATION	$446,960
														Subtotal = $446,960

Issue Date FY: 2022 ( Subtotal = $433,550 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	22	2/3/2022	NON-COMPETING CONTINUATION	$433,550
														Subtotal = $433,550

Issue Date FY: 2021 ( Subtotal = $433,552 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	21	4/20/2021	NON-COMPETING CONTINUATION	$433,552
														Subtotal = $433,552

Issue Date FY: 2020 ( Subtotal = $463,692 )
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	003	20	6/29/2020	COMPETING CONTINUATION	$148,797
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	001	20	1/15/2020	COMPETING CONTINUATION	$463,692
2020	2018	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	002	19	6/29/2020	COMPETING CONTINUATION	-$148,797
2020	2018	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	19	1/10/2020	COMPETING CONTINUATION	$0
														Subtotal = $463,692

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	001	19	1/30/2019	COMPETING CONTINUATION	$10,190
2019	2016	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	18	1/30/2019	EXTENSION WITH OR WITHOUT FUNDS	-$10,190
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $419,809 )
2018	2018	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	002	19	9/21/2018	COMPETING CONTINUATION	$419,809
2018	2016	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	001	18	9/21/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
2018	2016	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	18	12/11/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $419,809

Issue Date FY: 2016 ( Subtotal = $455,430 )
2016	2016	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	18	2/12/2016	EXTENSION WITH OR WITHOUT FUNDS	$455,430
														Subtotal = $455,430

Issue Date FY: 2015 ( Subtotal = $446,321 )
2015	2015	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	17	12/23/2014	NON-COMPETING CONTINUATION	$409,887
2015	2015	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	001	17	3/18/2015	NON-COMPETING CONTINUATION	$36,434
														Subtotal = $446,321

Issue Date FY: 2014 ( Subtotal = $502,534 )
2014	2014	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	002	16	9/12/2014	SUPPLEMENT FOR EXPANSION	$56,213
2014	2014	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	16	12/24/2013	NON-COMPETING CONTINUATION	$409,888
2014	2014	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	001	16	4/16/2014	NON-COMPETING CONTINUATION	$36,433
														Subtotal = $502,534

Issue Date FY: 2013 ( Subtotal = $519,034 )
2013	2013	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	15	12/6/2012	COMPETING CONTINUATION	$519,034
														Subtotal = $519,034

Issue Date FY: 2011 ( Subtotal = $365,904 )
2011	2011	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	14	5/17/2011	NON-COMPETING CONTINUATION	$365,904
														Subtotal = $365,904

Issue Date FY: 2010 ( Subtotal = $481,173 )
2010	2010	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Trans-NIH Recovery Act Research Support	000	12	1/29/2010	SUPPLEMENT FOR EXPANSION	$100,023
2010	2010	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	001	13	5/20/2010	NON-COMPETING CONTINUATION	$381,150
														Subtotal = $481,173

Issue Date FY: 2009 ( Subtotal = $385,000 )
2009	2009	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	12	5/13/2009	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2008 ( Subtotal = $438,358 )
2008	2008	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97201	MULTNOMAH	USA	Vision Research	000	11	5/19/2008	OTHER REVISION	$438,358
														Subtotal = $438,358

Grand Total All Awards = $5,791,317

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Herpes simplex virus egress from neurons into axons mediated by HSV membrane proteins gE/gI and US9 and axonal transport by kinesin motors.

Award Number: R01EY018755

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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