Inflammation in mertk-dependent retinitis pigmentosa

Ended Project Grant Awarded Last action

Award ID
R01EY034003
Recipient
Awarding agency
Obligated
$5,310,642

Award facts

Assistance listing
93.867 Vision Research
Completion date
Place of performance
New Haven, CT 06519, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
The biological process heretofore implicated in mertk loss-of-function-associated retinitis pigmentosa (RP) is defective phagocytosis of shed photoreceptor outer segments (POS) by retinal pigment epithelium (RPE) leading to photoreceptor (PR) degeneration. Here we propose a shift in this paradigm. We have demonstrated that the precise genetic ablation of mertk in mice (mertk -/- V2) results in deficient phagocytosis, but not PR degeneration. Furthermore, PR degeneration in the original mertk knockout (mertk -/- V1 that is hypomorphic from TYRO3) or mertk -/- V2 TYRO3 -/- V2 mice is associated with RPE inflammation. Therefore, we hypothesize that loss of mertk anti- inflammatory signaling in the RPE is a critical event leading to RP. To test this hypothesis, we propose to (i) conditionally ablate mertk in TYRO3 -/- RPE to test if this recapitulates RPE inflammation seen in germline mertk - /- V1 and mertk -/- V2 TYRO3 -/- V2 mice. An alternate possibility, RPE inflammation when mertk is conditionally ablated in TYRO3 -/- RPE notwithstanding, is that inflammation is a secondary consequence of loss of mertk-mediated phagocytosis and the consequent build-up of POS debris. We do not see POS build up even at 6 months in mertk -/- V2 or mertk -/- V3 mice. We also detect RPE inflammation before eye opening (at P10) and thus inflammation in the absence of mertk is likely primary. To directly test this, (II) we have generated a unique set of mouse models wherein either the phagocytosis or anti-inflammatory signaling function of mertk has been exclusively mutated, leaving the remaining function intact. These mouse models will allow US to definitively test the outcome of loss of mertk-mediated phagocytosis alone in PR degeneration, as well as uncouple the effects of loss of mertk anti-inflammatory signaling alone from that of loss of mertk-mediated phagocytosis. Complementing these studies, we will test the orthologous mutations in differentiated human primary RPE in terms of their effect on inducing RPE inflammation in presence or absence of POS. If inflammation underlies the etiology of mertk loss-of-function-associated RP, can IT be therapeutically targeted to protect against vision loss? (III) we have obtained promising preliminary data that the FDA-approved JAK1/2 inhibitor ruxolitinib reduces inflammatory gene expression in the mertk -/- V1 RPE and the severity of PR degeneration in mertk -/- V1 mice. Building on this proof-of-concept, we will optimize the ruxolitinib regimen (dose and duration of treatment) through dose- escalation studies to determine maximum protection against PR degeneration and vision loss. Taken together, these three independent, orthogonal approaches are expected to reveal mechanistic insight supporting a novel role of inflammation within the RPE itself as causally relevant to mertk loss-of-function-associated RP, as well as, provide a therapeutic avenue using small molecule JAK1/2 inhibitors ("jakinibs") already in clinical use for this severe, early-onset form of RP.

Transactions

Action Obligated Date
Amendment $0
Amendment $640,479
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Amendment $663,495
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Amendment $679,733
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Original award $679,733
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Subawards

Subrecipient Amount Awarded
Fordham University Inflammation in MERTK-dependent retinitis pigmentosa (R01EY034003) $230,795
Fordham University Dr. Finnemann will serve as the co-PI of the proposed project. In this capacity, her activities will include participation and guidance of her research team… $229,082

Quick answers

Who received award R01EY034003?

R01EY034003 was awarded to Yale Univ by National Eye Institute (National Institutes of Health) on September 1, 2023.

How much is award R01EY034003 worth?

$5,310,642 has been obligated on R01EY034003.

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