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Inflammation is a driver of newt lens regeneration

Award Number: R21EY033916
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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Inflammation is a driver of newt lens regeneration - Newts are one of the closest living relatives to mammals that retain full regenerative capabilities throughout their entire lifetime. Eguchi et al., demonstrated that the lens of the newt could be repeatedly removed 18 times over the course of 16 years and the last lens regenerated as perfectly as the first. This ability in newts is remarkable considering that humans have a high risk of developing posterior capsule opacification after a single cataract surgery. As a result, we thought for decades that newts were impervious to fibrotic disease. However, our preliminary data demonstrates macrophage depletion not only prevented lens regeneration but it also induced a fibrotic-like response after a single injury in the newt eye. We also found that treatment with the anti-inflammatory drug dexamethasone prevented lens regeneration but failed to induce a fibrotic response to injury. This highlights a truly unique role of the newt macrophage in preventing fibrotic disease. It also suggests that while inflammation and macrophages are necessary for regeneration in the newt, they have unique functions. Based on our preliminary data and work done in zebrafish, our hypothesis is that inflammation is required to trigger iris pigmented epithelial (IPE) cell reprogramming and that macrophages place limits on the inflammatory potential of the injury site. Thereby the absence of macrophages would be associated with a fibrotic response to injury resulting from uncontrolled inflammation triggering the recruitment and differentiation of myofibroblasts and aberrant extracellular matrix deposition. To test these hypotheses, we will characterize the magnitude and duration of the inflammatory response in the newt eye, the impact of dexamethasone and macrophage depletion on IPE cell apoptosis, proliferation, and markers of IPE cell reprogramming. We will also characterize macrophage polarization states and their transition from M1 to M2 phenotypes during the inflammatory response. Finally, the type of fibrotic injury induced by macrophage depletion will be further characterized as well as possible mechanisms leading to its formation. Recent work in mice and humans has demonstrated an inherent plasticity in macrophage function since they are highly programmable through manipulation of their local microenvironment. Our long term goal is to characterize factors in the newt microenvironment that instruct an anti-fibrotic response from newt macrophages that could be capable of eliciting similar functions in human macrophages as a treatment or prevention strategy for fibrotic 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 = $180,625 )
2023	2023	MIAMI UNIVERSITY	501 E HIGH ST	OXFORD	OH	45056	BUTLER	USA	Vision Research	000	2	8/23/2023	NON-COMPETING CONTINUATION	$180,625
														Subtotal = $180,625

Issue Date FY: 2022 ( Subtotal = $216,750 )
2022	2022	MIAMI UNIVERSITY	501 E HIGH ST	OXFORD	OH	45056	BUTLER	USA	Vision Research	000	1	9/16/2022	NEW	$216,750
														Subtotal = $216,750

Grand Total All Awards = $397,375

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Inflammation is a driver of newt lens regeneration

Award Number: R21EY033916

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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