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Novel investigation of the mechanism of Bax Modulation

Award Number: F31CA186672
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/01/2014
PERIOD OF PERFORMANCE END DATE: 06/30/2017

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Novel investigation of the mechanism of Bax Modulation - DESCRIPTION (provided by applicant): Apoptosis plays a critical role in maintaining normal tissue homoeostasis in multicellular organisms. Dysregulation of apoptosis can result in an imbalance of normal homeostasis contributing to diseases such as cancer and neurodegenerative diseases. Biochemical and genetic studies have revealed a prominent role for the BCL-2 protein family in regulating the commitment of the cell to mitochondrial apoptosis. Pro-apoptotic BAX is an executioner protein of the BCL-2 family that represents the gateway to mitochondrial apoptosis. In healthy mammalian cells, BAX is found in its inactive form in the cytosol. Following cellular stresses that induce apoptosis signaling, BAX translocates to the mitochondria where it inserts into the mitochondrial outer membrane and induces membrane permeabilization. Despite recent advances in understanding the structure, function and interactions of BAX, we do not fully understand precisely how cytosolic BAX is activated by BH3-only protein BIM or how it is kept inhibited in the cytosol. Here, we propose to intelligently investigate the mechanism of BAX modulation using an interdisciplinary approach including biochemical, biophysical, structural and cellular studies. Our specific aims are: 1.) To investigat the mechanism of BAX interaction and activation by BIM. For this aim, we will produce functional recombinant BIM for biochemical and structural studies. Once produced, we will determine the functional activity of BIM in BAX in vitro and in-cell activation studies. Finally, w will investigate the structural mechanism of BIM-BAX interaction. 2.) To examine the inhibition mechanism of BAX using synthetic antibodies. To accomplish our goals for this aim, we will first screen and evaluate the ability of phage display selected antibodies to bind to BAX. We will then evaluate the function of the selected BAX specific antibodies in binding and activation studies of BAX. Finally, we will determine the interaction site on BAX and the structural basis of BAX inhibition by the selected BAX specific inhibitory antibodies. With the mentorship of Dr. Evripidis Gavathiotis and Dr. Steven Almo, I will be able to accomplish the goals for the proposed research training and provide important knowledge for understanding and targeting BAX regulation while acquiring new skills and knowledge in structural biology, biophysics, biochemistry and cell biology of cell death. Furthermore, I will expand my training in communication skills, grant writing, scientific manuscript writing, mentoring, teaching and job application process, to further enhance my future career goals as a physician-scientist.


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: 2021 ( Subtotal = -$3,194 )
2021	2016	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Research Manpower	000	4	1/7/2021	NON-COMPETING CONTINUATION	-$3,194
														Subtotal = -$3,194

Issue Date FY: 2016 ( Subtotal = $48,576 )
2016	2016	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Cancer Research Manpower	004	4	7/5/2016	NON-COMPETING CONTINUATION	$48,576
2016	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Cancer Research Manpower	002	3	4/21/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$25,937
2016	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Cancer Research Manpower	000	3	1/27/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$444
2016	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cancer Research Manpower	003	2	4/21/2016	NON-COMPETING CONTINUATION	$25,937
2016	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cancer Research Manpower	001	2	1/27/2016	NON-COMPETING CONTINUATION	$444
														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	Cancer Research Manpower	000	2	6/26/2015	NON-COMPETING CONTINUATION	$48,120
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cancer Research Manpower	001	2	9/17/2015	NON-COMPETING CONTINUATION	-$48,120
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Cancer Research Manpower	002	3	9/18/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$48,120
														Subtotal = $48,120

Issue Date FY: 2014 ( Subtotal = $47,676 )
2014	2014	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cancer Research Manpower	000	1	7/1/2014	NEW	$42,676
2014	2014	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cancer Research Manpower	002	1	9/19/2014	NEW	$5,000
2014	2014	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cancer Research Manpower	001	1	7/1/2014	NEW	$0
														Subtotal = $47,676

Grand Total All Awards = $141,178

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Novel investigation of the mechanism of Bax Modulation

Award Number: F31CA186672

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/01/2014

PERIOD OF PERFORMANCE END DATE: 06/30/2017

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