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Elucidating mechanistic connections between guidance signaling, microtubule regulation, and growth cone steering

Award Number: R01MH109651
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract This proposal focuses on the fundamental question of how neuronal growth cones are guided to their targets. It has long been established that growth cone navigation depends on regulated changes in both F-actin and microtubule (MT) dynamics in response to guidance cues. However, the mechanisms by which these cues bring about specific changes in growth cone MT dynamics are unresolved. This proposal takes aim at that void, by investigating the function of the MT polymerase and ‘plus-end tracking protein’ (+TIP), XMAP215, along with its regulatory mechanisms. Our recently published data identified an ability for XMAP215 to bind directly to F-actin and promote MT extension into the growth cone. This is complemented by unpublished data that kinase signaling modulates the ability of XMAP215 to promote MT-F-actin interaction. Our data support a model in which XMAP215 mediates MT-F-actin coupling through structural domains distinct from those regulating MT polymerization, and that XMAP215 converts signals from upstream guidance cues into changes in cytoskeletal coordination, ultimately directing growth cone motility. We will test this in Xenopus laevis using an array of complementary cell-based and biochemical approaches. The specific aims are: Aim 1 – Identify the mechanism by which XMAP215 interacts with F-actin in vitro. We will determine the specific domain of XMAP215 that binds to F-actin as well as identify how the binding is regulated. We will produce a variety of deletion and phosphomutant XMAP215 proteins, and we will use a series of biochemical techniques including F-actin/MT co-sedimentation binding assays, multi-wavelength TIRF microscopy with in vitro cytoskeletal reconstitution assays, mass spectrometry, as well as EM experiments, to dissect the mechanism by which XMAP215 binds to F-actin in vitro. Aim 2 - Determine how regulation of XMAP215 interaction with F-actin modulates cytoskeletal dynamics and growth cone behaviors in cultured neurons. We will use structured illumination microscopy (SIM), spinning disk confocal microscopy, and quantitative imaging analysis of +TIP dynamics in cultured neurons, after expressing various XMAP215 mutants, to uncover new mechanistic insights into how XMAP215 regulates MT-F-actin interactions in growth cones during axon outgrowth. Aim 3 - Define how XMAP215 interaction with F-actin contributes to accurate axon guidance. We have discovered that normal XMAP215 levels are required for cultured growth cones to be repelled from the axon guidance cue, Slit2. We will use a combination of ex vivo and in vivo axon guidance assays to determine how growth cone steering is impacted by the ability of XMAP215 to facilitate MT-F-actin interactions. The results of these Aims will reveal the direct links between guidance cue signaling, kinase regulation of the only well-characterized MT polymerase (XMAP215), and cytoskeletal coordination, within the context of growth cone steering. As such, this proposed work has the potential to bring a long-needed mechanistic understanding to the question of how extracellular cues govern cytoskeletal dynamics to effectively steer growth cones during neurodevelopment.


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: 2025 ( Subtotal = $370,064 )
2025	2025	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL	BOSTON	MA	02118	SUFFOLK	USA	Mental Health Research Grants	000	9	11/22/2024	NON-COMPETING CONTINUATION	$370,064
														Subtotal = $370,064

Issue Date FY: 2024 ( Subtotal = $435,369 )
2024	2024	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL	BOSTON	MA	02118	SUFFOLK	USA	Mental Health Research Grants	001	8	8/15/2024	NON-COMPETING CONTINUATION	$43,537
2024	2024	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL	BOSTON	MA	02118	SUFFOLK	USA	Mental Health Research Grants	000	8	12/21/2023	NON-COMPETING CONTINUATION	$391,832
														Subtotal = $435,369

Issue Date FY: 2023 ( Subtotal = $440,994 )
2023	2023	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL STE 1	BOSTON	MA	02118	SUFFOLK	USA	Mental Health Research Grants	000	7	1/30/2023	NON-COMPETING CONTINUATION	$440,994
														Subtotal = $440,994

Issue Date FY: 2022 ( Subtotal = $447,288 )
2022	2022	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL STE 1	BOSTON	MA	02118	SUFFOLK	USA	Mental Health Research Grants	001	6	1/13/2022	COMPETING CONTINUATION	$448,494
2022	2022	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL STE 1	BOSTON	MA	02118	SUFFOLK	USA	Mental Health Research Grants	003	6	8/25/2022	COMPETING CONTINUATION	$313,925
2022	2020	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Mental Health Research Grants	000	5	12/14/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2020	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Mental Health Research Grants	002	5	8/25/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$313,925
2022	2019	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Mental Health Research Grants	004	4	8/29/2022	NON-COMPETING CONTINUATION	-$1,206
														Subtotal = $447,288

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Mental Health Research Grants	001	5	11/13/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$362,205
2021	2019	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Mental Health Research Grants	000	4	11/13/2020	NON-COMPETING CONTINUATION	-$362,205
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $448,609 )
2020	2020	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Mental Health Research Grants	001	5	8/21/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$448,609
2020	2019	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Mental Health Research Grants	000	4	8/21/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $448,609

Issue Date FY: 2019 ( Subtotal = $415,071 )
2019	2019	BOSTON COLLEGE, TRUSTEES OF	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Mental Health Research Grants	000	4	1/15/2019	NON-COMPETING CONTINUATION	$415,071
														Subtotal = $415,071

Issue Date FY: 2018 ( Subtotal = $402,928 )
2018	2018	BOSTON COLLEGE, TRUSTEES OF	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Mental Health Research Grants	000	3	1/31/2018	NON-COMPETING CONTINUATION	$352,125
2018	2018	BOSTON COLLEGE, TRUSTEES OF	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Mental Health Research Grants	003	3	7/13/2018	SUPPLEMENT FOR EXPANSION	$0
2018	2018	BOSTON COLLEGE, TRUSTEES OF	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Mental Health Research Grants	002	3	6/30/2018	SUPPLEMENT FOR EXPANSION	$11,678
2018	2018	BOSTON COLLEGE, TRUSTEES OF	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Mental Health Research Grants	001	3	6/17/2018	NON-COMPETING CONTINUATION	$39,125
														Subtotal = $402,928

Issue Date FY: 2017 ( Subtotal = $391,850 )
2017	2017	BOSTON COLLEGE, TRUSTEES OF	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Mental Health Research Grants	001	2	7/15/2017	NON-COMPETING CONTINUATION	$39,185
2017	2017	BOSTON COLLEGE, TRUSTEES OF	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Mental Health Research Grants	000	2	1/27/2017	NON-COMPETING CONTINUATION	$352,665
														Subtotal = $391,850

Issue Date FY: 2016 ( Subtotal = $407,175 )
2016	2016	BOSTON COLLEGE	140 Commonwealth Ave	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Mental Health Research Grants	000	1	4/28/2016	NEW	$407,175
														Subtotal = $407,175

Grand Total All Awards = $3,759,348

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Elucidating mechanistic connections between guidance signaling, microtubule regulation, and growth cone steering

Award Number: R01MH109651

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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