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Transcriptional Regulation of Retinal Development

Award Number: R01EY012020
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/1998
PERIOD OF PERFORMANCE END DATE: 06/30/2013

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Transcriptional Regulation of Retinal Development - DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand the molecular events that lead to the determination, differentiation and maintenance of different retinal cell types. During mammalian retinogenesis, seven classes of cells are specified from multipotent progenitors by the action of various intrinsic and extrinsic factors. Recent molecular genetic studies involving loss-of-function and gain-of-function approaches have uncovered a number of transcription factors as pivotal intrinsic regulators of retinogenesis. These factors are found to act at different developmental processes to establish progenitor multipotency, define progenitor competence, determine cell fates, and/or specify cell types and subtypes. Therefore, transcription factors play essential roles in controlling cell specification ad differentiation during retinogenesis. Despite these important advances, however, the molecular machinery and regulatory gene networks of many transcription factors involved in retinal development still remain poorly understood. In this application, experiments are proposed that will focus on the molecular and developmental events regulated by the Ptf1a and Tcfap2 transcription factors that lead to amacrine and horizontal cell differentiation. Our preliminary data and previous work have led us to propose that Ptf1a may form a crucial protein complex with the Rbpj cofactor to activate the expression of Tcfap2a and 2b, which in turn may be redundantly required for the differentiation of amacrine and horizontal cells. This project primarily aims to test this hypothesis by pursuing three specific aims: i) to investigate the requirement for a Ptf1a-Rbpj complex in specifying amacrine and horizontal cell fates. By analyzing retinal phenotypes in several different Ptf1a and Rbpj loss- of-function mouse models, we aim to test the working hypothesis that Ptf1a may form a Notch-independent protein complex with Rbpj to specify amacrine and horizontal cells during retinogenesis; ii) to test Tcfap2a and 2b as Ptf1a targets in amacrine and horizontal cell development. By misimpression, chromatin immunoprecipitation and phenotype rescue experiments, we aim to investigate whether Ptf1a is be able to directly activate Tcfap2a and 2b expression which in turn may mediate the Ptf1a function in amacrine and horizontal cell development; and iii) to analyze the role of Tcfap2a and 2b in differentiation of amacrine and horizontal cells. By misexpressing Tcfap2a and 2b in retinal progenitors and by simultaneous knockdown of both genes in the developing retina, we aim to test the working hypothesis that Tcfap2a and 2b may function as Ptf1a effectors genes that are redundantly required for amacrine and horizontal cell differentiation. The proposed studies are expected to elucidate the Ptf1a-modulated molecular machinery that controls amacrine and horizontal cell specification from retinal progenitors, thereby providing important insights into te regulatory gene network underlying the differentiation of different retinal cell types as well as a framework for future improvement of stem cell-based therapy to treat retinal degeneration. PUBLIC HEALTH RELEVANCE: The proposed studies aim to understand the molecular basis of retinal development, in particular, to identify transcription factors and build regulatory gene networks leading to the specification and differentiation of different retinal cell types from progenitors. Because differentiation of stem cells normally recapitulates the events that occur during embryogenesis, a better understanding of retinal progenitors and their development will enable us to better manipulate, maintain and exploit retinal stem cells for therapeutic purposes. Thus, the proposed research on retinal development may provide a framework for future improvement of stem cell-based therapy to treat human retinal degeneration.


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: 2014 ( Subtotal = $0 )
2014	2012	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Vision Research	000	14	1/13/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$11,093
2014	2012	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Vision Research	001	13	1/13/2014	COMPETING CONTINUATION	$11,093
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $0 )
2013	2012	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Vision Research	000	14	7/30/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$105,000
2013	2012	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Vision Research	001	13	7/30/2013	COMPETING CONTINUATION	-$105,000
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $300,517 )
2012	2012	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Vision Research	000	13	8/20/2012	COMPETING CONTINUATION	$300,517
														Subtotal = $300,517

Issue Date FY: 2010 ( Subtotal = $382,701 )
2010	2010	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Vision Research	000	12	12/8/2009	NON-COMPETING CONTINUATION	$347,910
2010	2010	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Vision Research	001	12	2/1/2010	NON-COMPETING CONTINUATION	$34,791
														Subtotal = $382,701

Issue Date FY: 2009 ( Subtotal = $386,667 )
2009	2009	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Vision Research	001	11	4/27/2009	NON-COMPETING CONTINUATION	$38,667
2009	2009	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Vision Research	000	11	11/18/2008	NON-COMPETING CONTINUATION	$348,000
														Subtotal = $386,667

Issue Date FY: 2008 ( Subtotal = $386,764 )
2008	2008	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Vision Research	000	10	12/20/2007	COMPETING CONTINUATION	$386,764
														Subtotal = $386,764

Issue Date FY: 2006 ( Subtotal = $336,568 )
2006	2006	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Vision Research	000	9	8/2/2006	NON-COMPETING CONTINUATION	$336,568
														Subtotal = $336,568

Issue Date FY: 2005 ( Subtotal = $344,667 )
2005	2005	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Vision Research	000	8	8/11/2005	NON-COMPETING CONTINUATION	$344,667
														Subtotal = $344,667

Issue Date FY: 2004 ( Subtotal = $344,667 )
2004	2004	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Vision Research	000	7	7/23/2004	NON-COMPETING CONTINUATION	$344,667
														Subtotal = $344,667

Issue Date FY: 2003 ( Subtotal = $344,667 )
2003	2003	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Vision Research	000	6	8/8/2003	NON-COMPETING CONTINUATION	$344,667
														Subtotal = $344,667

Issue Date FY: 2002 ( Subtotal = $344,667 )
2002	2002	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Vision Research	000	5	9/24/2002	COMPETING CONTINUATION	$344,667
														Subtotal = $344,667

Issue Date FY: 2001 ( Subtotal = $244,694 )
2001	2001	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Vision Research	000	4	2/5/2001	NON-COMPETING CONTINUATION	$244,694
														Subtotal = $244,694

Issue Date FY: 2000 ( Subtotal = $237,596 )
2000	2000	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Vision Research	000	3	1/19/2000	NON-COMPETING CONTINUATION	$237,596
														Subtotal = $237,596

Issue Date FY: 1999 ( Subtotal = $230,706 )
1999	1999	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Vision Research	000	2	1/14/1999	NON-COMPETING CONTINUATION	$230,706
														Subtotal = $230,706

Issue Date FY: 1998 ( Subtotal = $227,600 )
1998	1998	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Vision Research	000	1	1/28/1998	NEW	$227,600
														Subtotal = $227,600

Grand Total All Awards = $4,112,481

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Transcriptional Regulation of Retinal Development

Award Number: R01EY012020

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/1998

PERIOD OF PERFORMANCE END DATE: 06/30/2013

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