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The 3D-Structures of the Immunoglobulin Heavy Chain Locus

Award Number: R01AI082850
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2009
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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The 3D-Structures of the Immunoglobulin Heavy Chain Locus - Antibodies are generated by somatic recombination involving variable (V), diversity (D) and joining (J) gene segments. During the previous grant cycle, we initiated studies aimed to visualize VH-DHJH interactions in live cells. Using single color labeling we were able to track the trajectories adopted by VH and DHJH elements. We found that VH and DHJH elements were subjected to fractional Langevin motion, in which VH and DHJH elements bounce back and forth in a spring-like fashion. However, since only a single genomic region was marked, this approach did not permit us to directly monitor VH-DHJH interactions. To directly visualize VH- DHJH encounters we developed a novel approach. We generated BCR-ABL transformed pro- B cell lines that carried tandem arrays of wild-type TET-operator and mutant TET-operator binding sites in the VH and DHJH regions, respectively. To mark the VH and DHJH regions these cells were transduced with virus expressing WT-TET GFP and MUT-TET SNAP-TAG. The results were surprising. VH-DHJH motion was severely sub-diffusive. We found that VH regions were trapped in distinct chromatin configurations that were remarkably stable (<60 minutes). Only VH regions located nearby DHJH regions had a chance for a VH-DHJH encounter. Comparison of simulated and experimental data suggested that such severely sub-diffusive motion was imposed by geometric confinement (loop domains) and phase separation/gelation (reversible cross-links within VH-DHJH and DH-JH loop domains). A caveat of these studies is that they were performed using BCR-ABL transformed pro-B cells. Here we propose to perform and extend these studies using primary pre-pro-B and pro-B cells. Specifically, we would track VH-DHJH motion but now in primary B cell progenitors. We would describe VH-DHJH motion in physical terms, including diffusion coefficients, scaling exponents, velocities and spatial confinement. We would image across long-time scales to examine how long VH and DHJH regions are trapped in distinct configurations and determine when (timing) and how (speed) such configurations change. We would measure first-encounter times as well as pairing times. We would examine whether transcriptional regulators and chromatin remodelers modulate VH-DHJH motion and first-encounter times. We would identify critical residues in RAG1 that would dictate pairing times. We would visualize VDJ recombination in live cells. Data obtained from these experiments would reveal whether and how space and time intersect to modulate the motion of paired coding and regulatory elements.


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 = $380,263 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	15	5/24/2024	NON-COMPETING CONTINUATION	$38,026
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	15	2/22/2024	NON-COMPETING CONTINUATION	$342,237
														Subtotal = $380,263

Issue Date FY: 2023 ( Subtotal = $380,965 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	14	1/31/2023	NON-COMPETING CONTINUATION	$380,965
														Subtotal = $380,965

Issue Date FY: 2022 ( Subtotal = $381,633 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	13	2/11/2022	NON-COMPETING CONTINUATION	$381,633
														Subtotal = $381,633

Issue Date FY: 2021 ( Subtotal = $381,890 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	12	3/4/2021	NON-COMPETING CONTINUATION	$381,890
2021	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	10	12/10/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $381,890

Issue Date FY: 2020 ( Subtotal = $381,730 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	11	3/16/2020	COMPETING CONTINUATION	$381,730
														Subtotal = $381,730

Issue Date FY: 2018 ( Subtotal = $348,750 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	10	2/2/2018	NON-COMPETING CONTINUATION	$348,750
														Subtotal = $348,750

Issue Date FY: 2017 ( Subtotal = $348,750 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	9	2/17/2017	NON-COMPETING CONTINUATION	$348,750
														Subtotal = $348,750

Issue Date FY: 2016 ( Subtotal = $348,750 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	8	2/23/2016	NON-COMPETING CONTINUATION	$348,750
														Subtotal = $348,750

Issue Date FY: 2015 ( Subtotal = $348,750 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	7	1/9/2015	NON-COMPETING CONTINUATION	$348,750
														Subtotal = $348,750

Issue Date FY: 2014 ( Subtotal = $348,750 )
2014	2014	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	6	6/9/2014	COMPETING CONTINUATION	$34,875
2014	2014	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	6	12/27/2013	COMPETING CONTINUATION	$313,875
														Subtotal = $348,750

Issue Date FY: 2013 ( Subtotal = $284,680 )
2013	2013	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	5	5/31/2013	NON-COMPETING CONTINUATION	$12,114
2013	2013	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	2/7/2013	NON-COMPETING CONTINUATION	$272,566
														Subtotal = $284,680

Issue Date FY: 2012 ( Subtotal = $302,851 )
2012	2012	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	2/23/2012	NON-COMPETING CONTINUATION	$302,851
														Subtotal = $302,851

Issue Date FY: 2011 ( Subtotal = $302,851 )
2011	2011	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	3	6/8/2011	NON-COMPETING CONTINUATION	$27,532
2011	2011	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	2/4/2011	NON-COMPETING CONTINUATION	$275,319
														Subtotal = $302,851

Issue Date FY: 2010 ( Subtotal = $452,232 )
2010	2010	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	2/25/2010	NON-COMPETING CONTINUATION	$305,910
2010	2010	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Trans-NIH Recovery Act Research Support	001	2	8/9/2010	SUPPLEMENT FOR EXPANSION	$146,322
														Subtotal = $452,232

Issue Date FY: 2009 ( Subtotal = $386,250 )
2009	2009	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	2/9/2009	NEW	$309,000
2009	2009	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	1	9/3/2009	NEW	$77,250
														Subtotal = $386,250

Grand Total All Awards = $5,379,095

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The 3D-Structures of the Immunoglobulin Heavy Chain Locus

Award Number: R01AI082850

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2009

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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