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Extra-coding features of mRNA are essential for hERG channel function

Award Number: F30HL126283
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/05/2015
PERIOD OF PERFORMANCE END DATE: 08/04/2019

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Extra-coding features of mRNA are essential for hERG channel function - ¿ DESCRIPTION (provided by applicant): Extra-coding features of mRNA are essential for hERG channel function This hERG potassium channel plays an essential role in cardiac repolarization, and malfunction of this channel caused by mutation leads to Long QT Syndrome, type 2 (LQT2). LQT2 results in delayed repolarization of the cardiac myocyte, leading to ventricular arrhythmias, syncope and sudden death. There are over 600 documented mutations in KCNH2 associated with Long QT syndrome and these mutations occur throughout the length of the gene, without definitive mutational hotspots. Little investigation has been focused on what causes the hERG channel to be intolerant to mutation. Our hypothesis is that "extra-coding" features on the mRNA level, such as GC content, rare codon usage and mRNA structure contribute to determining correct protein synthesis of the hERG channel, and that mutational changes that disrupt these features lead to Long QT Syndrome. Previous studies from our lab support this hypothesis. HERG-CM, a codon modified version of the hERG mRNA, was made with reduced GC content (51%) and decreased use of rare codons, while maintaining the exact amino acid sequence. hERG-CM protein was translated and trafficked differently than the native hERG (hERG-NT) channel. To further understand the mechanism behind these observations, Ribosomal Profiling will be used to investigate differences in ribosomal movement across the hERG-NT and - CM mRNA. Capillary Electrophoresis will also be used to investigate structural differences between these two mRNAs. We hypothesize that the sites of ribosomal pausing, caused by rare codons or mRNA structure, allow for important secondary and tertiary structure formation and trafficking of the HERG protein. These pausing locations in the hERG-NT and -CM mRNAs will be investigated, and correlated with known LQT2 mutations to investigate their impact on Long QT pathogenesis. The influence of these extra-coding features of the mRNA on protein folding will also be investigated, through pulse proteolysis, to examine differences in intermediate or final folded structure. hERG-CM and hERG-NT protein function will also be assessed through electrophysiology. Successful completion of this project will provide novel information on how mRNA impacts not only the primary structure of a protein, but also the folding intermediates, translational efficiency, trafficking efficiency, and function of the protei product. Ongoing studies will have implications for evaluation and treatment of hereditary and acquired arrhythmias.


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: 2019 ( Subtotal = $0 )
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cardiovascular Diseases Research	000	5	3/1/2019	NON-COMPETING CONTINUATION	-$29,561
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cardiovascular Diseases Research	001	6	3/2/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$29,561
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $51,815 )
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cardiovascular Diseases Research	001	5	8/2/2018	NON-COMPETING CONTINUATION	$49,524
2018	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cardiovascular Diseases Research	000	2	3/29/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,291
														Subtotal = $51,815

Issue Date FY: 2017 ( Subtotal = $49,044 )
2017	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cardiovascular Diseases Research	000	4	7/28/2017	NON-COMPETING CONTINUATION	$49,044
														Subtotal = $49,044

Issue Date FY: 2016 ( Subtotal = $48,576 )
2016	2016	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Cardiovascular Diseases Research	002	3	7/8/2016	NON-COMPETING CONTINUATION	$48,576
2016	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cardiovascular Diseases Research	000	1	11/5/2015	NEW	-$44,110
2016	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Cardiovascular Diseases Research	001	2	11/6/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$44,110
														Subtotal = $48,576

Issue Date FY: 2015 ( Subtotal = $48,120 )
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cardiovascular Diseases Research	000	1	8/5/2015	NEW	$0
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cardiovascular Diseases Research	001	1	8/5/2015	NEW	$48,120
														Subtotal = $48,120

Grand Total All Awards = $197,555

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Extra-coding features of mRNA are essential for hERG channel function

Award Number: F30HL126283

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/05/2015

PERIOD OF PERFORMANCE END DATE: 08/04/2019

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