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Elucidating the mechanism and consequences of aberrant cyclin D1 gene expression

Award Number: R01GM135361
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Elucidating the mechanism and consequences of aberrant cyclin D1 gene expression - ABSTRACT Some genes take drastic measures to force their aberrant expression. As an example, the gene cyclin D1 which is not normally present in B-cell lymphocytes is expressed in the blood cancer Mantle Cell Lymphoma (MCL). MCL is the most aggressive of all B-cell malignancies and a chromosomal translocation event, that pre-dates the disease, activates the cyclin D1 promoter is the initiating lesion in the transformation of normal B-cells. Once expressed, the transcribed cyclin D1 message (pre-mRNA) undergoes further processing which enables it to shorten it's 3'untraslated region (3'UTR) thus increasing the half-life of the transcript. The expression of cyclin D1 in MCL facilitates a hyper-proliferative phenotype and increases the genetic instability and chromosomal abnormalities of B-cells. In our prior work we identified a novel fusion gene in MCL cell lines and patient samples where cyclin D1 is joined to another gene thus resulting in a truncated 3'UTR. The goal of this project is to determine the molecular mechanisms that drive the shortening of the 3'UTR of cyclin D1 as well as the effects of the cyclin D1 driven chromosomal translocation events. In this proposal we will determine how the sequences found in the pre-mRNA of cyclin D1 as well as proteins involved in 3'end processing play a role in optimizing the expression of cyclin D1 in MCL (Aim 1). We will also systematically identify fusion genes, which result from chromosomal translocation events, using third generation sequencing technology which allows us to get full length gene transcripts (Aim 2). Although chromosomal translocations are known to occur with a high degree of frequency in MCL, apart from serendipity discovery in individual case studies, little effort has been put into identifying fusion genes on a global scale making this type of research innovative. Furthermore, our study will determine the molecular basis of abnormal 3'end formation will answer a basic question in the field. This will have a positive impact by establishing better understanding of disease causing genes are expressed in human cells and will allow for more effective strategies to detect and treat disease.


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 = $278,722 )
2024	2024	BUTLER UNIVERSITY	4600 SUNSET AVE	INDIANAPOLIS	IN	46208	MARION	USA	Biomedical Research and Research Training	000	5	7/9/2024	NON-COMPETING CONTINUATION	$278,722
														Subtotal = $278,722

Issue Date FY: 2023 ( Subtotal = $280,963 )
2023	2023	BUTLER UNIVERSITY	4600 SUNSET AVE	INDIANAPOLIS	IN	46208	MARION	USA	Biomedical Research and Research Training	001	4	7/19/2023	NON-COMPETING CONTINUATION	$280,963
2023	2021	BUTLER UNIVERSITY	4600 SUNSET AVE	INDIANAPOLIS	IN	46208	MARION	USA	Biomedical Research and Research Training	000	2	10/24/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $280,963

Issue Date FY: 2022 ( Subtotal = $281,766 )
2022	2022	BUTLER UNIVERSITY	4600 SUNSET AVE	INDIANAPOLIS	IN	46208	MARION	USA	Biomedical Research and Research Training	000	3	9/20/2022	NON-COMPETING CONTINUATION	$281,766
														Subtotal = $281,766

Issue Date FY: 2021 ( Subtotal = $272,041 )
2021	2021	BUTLER UNIVERSITY	4600 SUNSET AVE	INDIANAPOLIS	IN	46208	MARION	USA	Biomedical Research and Research Training	000	2	8/3/2021	NON-COMPETING CONTINUATION	$272,041
														Subtotal = $272,041

Issue Date FY: 2020 ( Subtotal = $280,633 )
2020	2020	BUTLER UNIVERSITY	4600 SUNSET AVE	INDIANAPOLIS	IN	46208	MARION	USA	Biomedical Research and Research Training	000	1	7/30/2020	NEW	$280,633
														Subtotal = $280,633

Grand Total All Awards = $1,394,125

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Elucidating the mechanism and consequences of aberrant cyclin D1 gene expression

Award Number: R01GM135361

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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