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The Retinoblastoma corepressor family: precision targeting for discerning gene regulatory mechanisms in the Drosophila eye

Award Number: F31HD105410
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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The Retinoblastoma corepressor family: precision targeting for discerning gene regulatory mechanisms in the Drosophila eye - PROJECT SUMMARY/ABSTRACT Retinoblastoma is a rare pediatric cancer that is caused by loss of both copies of the retinoblastoma (Rb) tumor suppressor gene. Rb is a highly conserved and critical transcription factor for the proper regulation of gene expression in eukaryotes. Mutations in Rb have also been observed in many human cancers including breast and lung cancer. In humans, the Rb family comprises Rb, p107, and p130, which exhibit both overlapping and non-redundant roles in gene regulation. Similarly, the Drosophila lineage experienced a gene duplication event leading to the expression of the Rbf1 and Rbf2 paralogs. The significance of the multiplicity of the Rb family and their division of labor in regulating gene expression in different contexts is not clear. Their activity has been studied in the context of specific promoters; however, we lack deeper mechanistic understanding of these factors in the context of normal tissues, in development. This proposal will investigate the tissue-specific gene regulatory activities of retinoblastoma family proteins using the fly model system. We hypothesize that the Rb family has diversified to have gene-specific activities through differential targeting to promoters and through different repression activities. In Aim 1, we will investigate how Rb paralogs exhibit mechanistically different transcriptional control while in Aim 2 we will determine how regulation of the Rbf1 protein itself controls promoter-specific repression. We will use our newly developed method for highly precise targeting of Rb paralogs to diverse gene promoters through Rb fusions to a nuclease dead Cas9. This powerful tool allows for direct comparison of the Rb family members in a developmental system to study their gene- and tissue-specific activities. Using this tool, we will determine the differences between Rbf1 and Rbf2 impact on gene expression, and differences in modulation of the chromatin environment. This project will be carried out at Michigan State University in the lab of Dr. David Arnosti as part of a comprehensive academic and professional training plan to prepare the applicant for a career as an independent research scientist investigating gene regulation in the context of disease. With the completion of the proposed work, the results will uncover the mechanisms of gene regulation by Rb family proteins, which will improve our understanding of why certain tissues are especially sensitive to inactivation of Rb. Understanding the mechanisms of Rb-mediated gene regulation and its activity as a transcriptional repressor will allow for the development of gene therapies to treat Retinoblastoma and other cancer types.


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: 2024 ( Subtotal = $0 )
2024	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Child Health and Human Development Extramural Research	000	2	6/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $33,800 )
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Child Health and Human Development Extramural Research	000	2	8/1/2022	NON-COMPETING CONTINUATION	$33,800
														Subtotal = $33,800

Issue Date FY: 2021 ( Subtotal = $32,967 )
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Child Health and Human Development Extramural Research	001	1	7/14/2021	NEW	$0
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Child Health and Human Development Extramural Research	000	1	7/14/2021	NEW	$32,967
														Subtotal = $32,967

Grand Total All Awards = $66,767

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The Retinoblastoma corepressor family: precision targeting for discerning gene regulatory mechanisms in the Drosophila eye

Award Number: F31HD105410

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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