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Regulatory mechanisms for retinal ganglion cell genesis

Award Number: R01EY020545
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2011
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Regulatory mechanisms for retinal ganglion cell genesis - Project Summary/Abstract How individual retinal cell types arise from retinal progenitor cells (RPCs) is an active field of research, as it is critical to understanding the generation of cellular diversity in the retina and developing therapeutic strategies to treat degenerative retinal diseases. Many transcription factors involved in the generation of individual retinal cell types have been identified. Single-cell technologies have led to unprecedented progress in discerning the cellular relationships of the different lineage trajectories and the underlying changes in the epigenetic landscape. The roles of individual transcription factors in shaping the epigenetic landscape to drive multipotent RPCs to specific fates are also beginning to be revealed. A major finding from the single-cell RNA-seq studies is that all the retinal lineages undergo a shared state, namely transitional RPCs (tRPCs), before fate determination. tRPCs are multipotent and co-express genes involved in the different retinal cell types such as Atoh7 for RGCs and Otx2 and Neurod1 for photoreceptors. Our mapping of binding sites for Atoh7 and Otx2 by CUT&Tag suggests a general paradigm via which the co-expressed transcription factors compete at enhancers of lineage-specific genes to drive tRPCs to different cell fates. The focus of our lab has been on the mechanisms controlling RGC genesis. In this application, we propose to address several key knowledge gaps regarding the emergence of the RGC lineage from tRPCs. The first is the missing branch of upstream input as indicated by our scRNA- seq analysis of the Atoh7-null retina. We hypothesize that the SoxC factors fulfill this role by function in parallel with Atoh7 to promote RGC genesis based on previous findings on the roles of the SoxC factors in RGC genesis. The second gap we aim to address is the molecular basis for the specificity of Atoh7 for the RGC lineage. This is based on the fact that several proneural bHLH transcription factors, including Atoh7 and Neurod1, which all bind to the E box motif, are co-expressed in tRPCs, but only Atoh7 promotes RGC formation. Using ectopic expression in retinal explants, we have obtained compelling evidence which suggests that the RGC-specificity of Atoh7 resides in the bHLH domain. We will further explore the molecular basis for the RGC specificity of Atoh7 in vivo using knockin mouse lines. Lastly, we will investigate the regulatory mechanisms leading to the fixation of the RGC fate. We will leverage the candidate enhancers identified from our scATAC-seq and CUT&Tag experiments for the key RGC specific transcription factor gene Pou4f2 and examine their contributions to the eventual expression of Pou4f2. Our experiments are designed to address these gaps using a combined approach of mouse genetics, immunohistochemistry, genomics, transcriptomics, and single cell techniques. These proposed experiments aim to understand key gene regulatory events controlling the emergence of the RGC lineage from tRPCs. The findings will lead to further insights into the molecular basis underpinning the cellular diversity in the retina and offer guidance for developing strategies to treat degenerative retinal 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: 2026 ( Subtotal = $459,457 )
2026	2026	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Vision Research	000	14	5/6/2026	NON-COMPETING CONTINUATION	$459,457
														Subtotal = $459,457

Issue Date FY: 2025 ( Subtotal = $459,457 )
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Vision Research	000	13	5/23/2025	NON-COMPETING CONTINUATION	$459,457
														Subtotal = $459,457

Issue Date FY: 2024 ( Subtotal = $459,457 )
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Vision Research	001	12	6/3/2024	NON-COMPETING CONTINUATION	$459,457
2024	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Vision Research	000	10	4/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $459,457

Issue Date FY: 2023 ( Subtotal = $473,311 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Vision Research	000	11	7/7/2023	COMPETING CONTINUATION	$473,311
														Subtotal = $473,311

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Vision Research	000	10	8/19/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $379,954 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Vision Research	000	10	5/27/2021	NON-COMPETING CONTINUATION	$379,954
														Subtotal = $379,954

Issue Date FY: 2020 ( Subtotal = $391,977 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Vision Research	000	9	5/26/2020	NON-COMPETING CONTINUATION	$391,977
														Subtotal = $391,977

Issue Date FY: 2019 ( Subtotal = $392,533 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Vision Research	000	8	5/16/2019	NON-COMPETING CONTINUATION	$392,533
														Subtotal = $392,533

Issue Date FY: 2018 ( Subtotal = $393,048 )
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Vision Research	000	7	6/18/2018	NON-COMPETING CONTINUATION	$393,048
														Subtotal = $393,048

Issue Date FY: 2017 ( Subtotal = $390,903 )
2017	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Vision Research	001	6	8/29/2017	COMPETING CONTINUATION	$390,903
2017	2015	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Vision Research	000	5	6/2/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $390,903

Issue Date FY: 2015 ( Subtotal = $381,294 )
2015	2015	SUNY, BUFFALO	219 MARKLE HALL	BUFFALO	NY	10016		USA	Vision Research	000	5	2/19/2015	NON-COMPETING CONTINUATION	$381,294
														Subtotal = $381,294

Issue Date FY: 2014 ( Subtotal = $381,294 )
2014	2014	SUNY, BUFFALO	219 MARKLE HALL	BUFFALO	NY	10016		USA	Vision Research	000	4	2/26/2014	NON-COMPETING CONTINUATION	$381,294
														Subtotal = $381,294

Issue Date FY: 2013 ( Subtotal = $369,622 )
2013	2013	SUNY, BUFFALO	219 MARKLE HALL	BUFFALO	NY	10016		USA	Vision Research	000	3	2/20/2013	NON-COMPETING CONTINUATION	$350,168
2013	2013	SUNY, BUFFALO	219 MARKLE HALL	BUFFALO	NY	10016		USA	Vision Research	001	3	6/25/2013	NON-COMPETING CONTINUATION	$19,454
														Subtotal = $369,622

Issue Date FY: 2012 ( Subtotal = $389,076 )
2012	2012	SUNY, BUFFALO	219 MARKLE HALL	BUFFALO	NY	10016		USA	Vision Research	000	2	2/29/2012	NON-COMPETING CONTINUATION	$389,076
														Subtotal = $389,076

Issue Date FY: 2011 ( Subtotal = $389,076 )
2011	2011	SUNY, BUFFALO	219 MARKLE HALL	BUFFALO	NY	10016		USA	Vision Research	000	1	2/22/2011	NEW	$389,076
														Subtotal = $389,076

Grand Total All Awards = $5,710,459

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Regulatory mechanisms for retinal ganglion cell genesis

Award Number: R01EY020545

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2011

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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