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DREAM Mediated Transcription Acts as a Biomarker for Pollutant Induced Calcium Signaling Disruption

Award Number: SC3GM132033
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Summary/Abstract Chemicals such as polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and triclosan alter cellular Ca2+ signaling acting through L-type voltage-sensitive Ca2+ channels (CaV1) and/or ryanodine receptors (RyR), which regulate the entry of Ca2+ from external sources or the release of Ca2+ from internal stores, respectively. These channels alone are central to the function of a vast number of cellular signaling processes and chemical disruption of these targets is correlated with altered dendritic growth, altered neuromuscular health, and altered learning and memory in exposed model organisms. The list of toxicants, and their receptor targets, that lead to such Ca2+ signaling disruption (CSD; used for disruption and disrupting) is currently unknown. However, based on structural similarities to known CSD compounds, we hypothesize that a large number of chemicals currently in use or in the environment are capable of CSD representing a need for high-throughput tools able to screen individual chemicals and complex environmental mixtures. Recent work has identified the downstream regulatory element antagonistic modulator (DREAM) which is the only Ca2+ sensor identified to date that binds speci¿cally to DNA and regulates transcription in a Ca2+-dependent manner. Thus the DREAM protein acts as a direct connection between changes in intracellular Ca2+- and gene transcription Our preliminary work demonstrates that select CSD compounds can alter DREAM mediated transcription in model cell lines representing a unique opportunity to establish a CSD screening assay. Here, we take a multi-tiered approach to extend our understanding of DREAM, in-light-of pollutant responses, by screening known and predicted CSD chemicals for their ability to drive DREAM transcription in luciferase transfected cell lines and evaluating the extent of DREAM mediated transcription or altered phenotypes in CSD exposed wildtype and DREAM knockout zebrafish. The proposed work will establish gene transcription as a toxic outcome due to CSD and lead to the development and validation of important cellular and animal tools able to cost and time effectively evaluate large numbers of compounds for CSD activity. This work has vast implications on the health of exposed organisms as DREAM is known to contribute to such processes as learning and memory, pain reception and endocrine signaling in the hypothalamus, pituitary and the thyroid gland and has been associated with Huntington’s disease, a myotrophic lateral sclerosis and type II diabetes. Understanding the role of CSD in these physiological and pathophysiological states would aid in pollutant associated risk assessment.


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: 2023 ( Subtotal = $108,413 )
2023	2023	CALIFORNIA STATE UNIVERSITY, LONG BEACH RESEARCH FOUNDATION	6300 E STATE UNIVERSITY DR STE 332	LONG BEACH	CA	90815	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	3/1/2023	NON-COMPETING CONTINUATION	$108,413
														Subtotal = $108,413

Issue Date FY: 2022 ( Subtotal = $108,413 )
2022	2022	CALIFORNIA STATE UNIVERSITY, LONG BEACH RESEARCH FOUNDATION	6300 E STATE UNIVERSITY DR STE 332	LONG BEACH	CA	90815	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	2/7/2022	NON-COMPETING CONTINUATION	$97,571
2022	2022	CALIFORNIA STATE UNIVERSITY, LONG BEACH RESEARCH FOUNDATION	6300 E STATE UNIVERSITY DR STE 332	LONG BEACH	CA	90815	LOS ANGELES	USA	Biomedical Research and Research Training	001	3	6/20/2022	NON-COMPETING CONTINUATION	$10,842
														Subtotal = $108,413

Issue Date FY: 2021 ( Subtotal = $108,413 )
2021	2021	CALIFORNIA STATE UNIVERSITY, LONG BEACH RESEARCH FOUNDATION	6300 E STATE UNIVERSITY DR STE 332	LONG BEACH	CA	90815	LOS ANGELES	USA	Biomedical Research and Research Training	000	2	2/25/2021	NON-COMPETING CONTINUATION	$108,413
														Subtotal = $108,413

Issue Date FY: 2020 ( Subtotal = $108,413 )
2020	2020	CALIFORNIA STATE UNIVERSITY, LONG BEACH RESEARCH FOUNDATION	6300 E STATE UNIVERSITY DR STE 332	LONG BEACH	CA	90815	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	4/4/2020	NEW	$108,413
														Subtotal = $108,413

Grand Total All Awards = $433,652

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DREAM Mediated Transcription Acts as a Biomarker for Pollutant Induced Calcium Signaling Disruption

Award Number: SC3GM132033

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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