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Promoting myelination of regenerating axons for vision restoration

Award Number: R01EY036220
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Promoting myelination of regenerating axons for vision restoration - Abstract/Project Summary Myelination facilitates rapid axonal conduction, enabling efficient communication across different parts of the nervous system. Demyelination associated with CNS trauma or diseases such as multiple sclerosis (MS) and glaucoma contributes significantly to behavioral deficits. Despite tremendous progress in understanding regulatory mechanisms of myelination, there are no pro-myelination treatments in the clinical setting. In our recent studies, using optic nerve/tract injury models, we discovered that injured axons could regenerate following intervention to elevate the regenerative ability of retinal ganglion cells (RGCs), yet these regenerated axons fail to be myelinated. Further, we showed that oligodendrocyte precursor cells (OPCs) do proliferate but fail to differentiate and mature into myelinating oligodendrocytes in response to ONC. With these unique models, we further demonstrated that blockade of muscarinic receptor 1 (M1R, or Chrm1) or GPR17 promoted OPC differentiation while depleting activated microglia facilitated the maturation or survival of newly formed oligodendrocytes. Thus, at least two overarching mechanisms contribute to the observed myelination failure: OPC intrinsic mechanisms preventing OPC differentiation, and microglia-relevant factors inhibiting the formation of mature oligodendrocytes by unknown mechanism(s). Importantly, treatments acting on these mechanisms promoted de novo myelination of regenerated axons and point to potential translatable pro- myelination strategies. In this application, following up with these initial findings, we will investigate the following questions: how do M1R and GPR17 regulate OPC differentiation? Do they work within the same signaling pathway(s)? How do activated microglia affect oligodendrocytes? Does treatment-induced de novo myelination improve behavioral outcome(s)? We expect that our studies will inform the mechanisms and therapeutic potential of myelination regeneration and visual restoration.


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: 2025 ( Subtotal = $560,851 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Vision Research	000	2	4/10/2025	NON-COMPETING CONTINUATION	$560,851
														Subtotal = $560,851

Issue Date FY: 2024 ( Subtotal = $560,851 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Vision Research	000	1	4/4/2024	NEW	$560,851
														Subtotal = $560,851

Grand Total All Awards = $1,121,702

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Promoting myelination of regenerating axons for vision restoration

Award Number: R01EY036220

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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