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Back to Basics: T Cellular Control of Nod2 in Uveitis

Award Number: R01EY025250
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2015
PERIOD OF PERFORMANCE END DATE: 02/29/2024

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Back to Basics: T Cellular Control of Nod2 in Uveitis - PROJECT SUMMARY: Uveitis is a complex set of diseases that together constitute ~15% of visual morbidity worldwide. For many patients, uveitis can be a chronic life-long disease for which therapies may manage painful inflammation, but do not provide a cure. For some with rheumatologic conditions, uveitis is also accompanied by diseases of the joint, skin, or gut. Thus there is an urgent, unmet need to define key mechanisms of uveitis because of its significant associated personal, social, and economic burdens. Innate immunity, as the first line of defense against microbial pathogens, is a response that must be tightly regulated to avoid excessive inflammation and tissue destruction. Such regulation is especially important in the eye, where multiple factors and processes act together to limit inflammation so as to preserve the delicate cells and tissues critical to vision. The body senses potentially pathogenic microbes in the environment via innate immune receptors, which are classified into distinct families such as Toll-like receptors (TLRs) or NOD-like receptors (NLRs). One NLR, Nod2, not only serves as an intracellular sensor of microbial and foreign motifs, but is causally linked to non-infectious granulomatous uveitis in Blau syndrome. Using a model of T cell-mediated uveitis, experimental autoimmune uveitis (EAU), an unexpected novel role was identified for Nod2 in protection against autoimmune uveitis. Such protection was found to be conferred by CD4+ T cells and involved Nod2 modulation of the pathogenic capacity of a subset of CD4+ T cells, Th17 cells, by controlling their production of the cytokine IL-17. Based on these findings, as well as additional key preliminary data, this proposal aims to systematically probe the spectrum of actions by which Nod2 could impact the evolution of disease-causing T cells responses. Using methodologies that encompass molecular, cellular, and whole animal evaluation, experiments will test the central hypothesis that Nod2 is a critical immunomodulator of autoreactive T cells that cause uveitis, and are organized in three Specific Aims: 1) Delve into how Nod2 alters the uveitogenic potential of individual or populations of CD4+ T cells; 2) Elucidate the effects of Nod2 on the internal operations of T cells that intersect with T-cell receptor (TCR) signaling and T cell function; and 3) Determine whether Nod2 influences T cell development and maturation of uveitogenic T cells. The role of Nod2 in autoimmune diseases is an area that has yet to be more fully clarified. This research could potentially open up new avenues of investigation that could ultimately result in novel strategies for therapeutic intervention of uveitis, as well as of other vision-threatening 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: 2023 ( Subtotal = $315,000 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	9	2/21/2023	NON-COMPETING CONTINUATION	$315,000
														Subtotal = $315,000

Issue Date FY: 2022 ( Subtotal = $305,550 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	8	4/28/2022	NON-COMPETING CONTINUATION	$305,550
														Subtotal = $305,550

Issue Date FY: 2021 ( Subtotal = $305,550 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	7	4/21/2021	NON-COMPETING CONTINUATION	$305,550
														Subtotal = $305,550

Issue Date FY: 2020 ( Subtotal = $315,000 )
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	6	7/6/2020	NON-COMPETING CONTINUATION	$315,000
														Subtotal = $315,000

Issue Date FY: 2019 ( Subtotal = $312,408 )
2019	2019	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	5	1/30/2019	COMPETING CONTINUATION	$312,408
2019	2018	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	001	4	6/26/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $312,408

Issue Date FY: 2018 ( Subtotal = $283,500 )
2018	2018	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	001	4	5/7/2018	NON-COMPETING CONTINUATION	$28,350
2018	2018	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	4	2/26/2018	NON-COMPETING CONTINUATION	$255,150
														Subtotal = $283,500

Issue Date FY: 2017 ( Subtotal = $283,500 )
2017	2017	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	3	2/8/2017	NON-COMPETING CONTINUATION	$255,150
2017	2017	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	001	3	7/17/2017	NON-COMPETING CONTINUATION	$28,350
														Subtotal = $283,500

Issue Date FY: 2016 ( Subtotal = $283,500 )
2016	2016	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	2	3/22/2016	NON-COMPETING CONTINUATION	$290,000
2016	2016	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	001	2	6/30/2016	NON-COMPETING CONTINUATION	-$6,500
														Subtotal = $283,500

Issue Date FY: 2015 ( Subtotal = $280,692 )
2015	2015	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	1	3/27/2015	NEW	$280,692
														Subtotal = $280,692

Grand Total All Awards = $2,684,700

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Back to Basics: T Cellular Control of Nod2 in Uveitis

Award Number: R01EY025250

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2015

PERIOD OF PERFORMANCE END DATE: 02/29/2024

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