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Mechanisms of intermittent hypoxia-induced motor recovery in persons with SCI

Award Number: R01HD081274
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2014
PERIOD OF PERFORMANCE END DATE: 02/28/2021

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Mechanisms of intermittent hypoxia-induced motor recovery in persons with SCI - DESCRIPTION (provided by applicant): Spinal cord injury (SCI) disrupts connections between the brain and spinal cord, causing devastating loss of mobility and independence. Most injuries are incomplete (iSCI), leaving intact at least some neural pathways to motor neurons that control movement. Although spontaneous plasticity in these spared pathways underlies some functional recovery, the extent of spontaneous recovery after iSCI is slow, variable and frustratingly limited. There is a critical need for new therapies that induce further improvements in persons with chronic iSCI. We recently demonstrated that repetitive exposure to acute intermittent hypoxia (rAIH), alone or in combination with walking training, stimulates motor recovery in persons with chronic iSCI. As an early stage investigator, I now propose to test four hypotheses concerning mechanisms of rAIH-induced motor recovery using multiple experimental approaches, including muscle electromyography, measurements of walking dynamics and leg strength, genotyping and pharmacological intervention. In Aim 1, we will focus on the neuromechanical bases of improved walking after rAIH, including increased motor gain (muscle activity) and coordination, as well as, reduced step-by-step variability. In Aim 2, we will test whether the functional benefits of rAIH when combined with training (strength or walking) are task-specific. We hypothesize that the cellular mechanisms that underlie the benefits of rAIH (alone or combined with training) in respiratory and non- respiratory motor function in rodent models applies also to humans with chronic, iSCI. Since AIH induces spinal motor plasticity in rats by a mechanism that requires serotonin-dependent synthesis of brain derived neurotrophic factor (BDNF), in Aim 3, we will explore the BDNF-dependence of rAIH-induced motor recovery by assessing the impact of extent of functional recovery in individuals with bdnf polymorphisms known to undermine spinal BDNF function in humans. Finally, concurrent activation of competing cellular cascades during AIH (initiated by serotonin and adenosine, respectively) undermines respiratory motor plasticity in rats. By removing the adenosine-dependent mechanism, greater functional plasticity can be achieved. Thus, in Aim 4, we hypothesize that, by pharmaceutically removing the adenosine constraint on rAIH-induced spinal plasticity via caffeine administration, the therapeutic efficacy of rAIH will improve, increasing its potential asa viable treatment to improve motor function. Each aim is supported by substantial preliminary data, suggesting that the proposed experiments will advance our understanding of mechanisms giving rise to rAIH-induced motor recovery after iSCI. An important goal guiding our research is to identify ways to optimize rAIH-induced plasticity, thereby promoting meaningful functional recovery in persons with chronic iSCI.


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: 2022 ( Subtotal = $0 )
2022	2018	SPAULDING REHABILITATION HOSPITAL (SRH) VOLUNTEER SERVICES,	300 FIRST AVE	CHARLESTOWN	MA	02129	SUFFOLK	USA	Child Health and Human Development Extramural Research	001	6	6/29/2022	NON-COMPETING CONTINUATION	-$2,946
2022	2018	SPAULDING REHABILITATION HOSPITAL (SRH) VOLUNTEER SERVICES,	300 FIRST AVE	CHARLESTOWN	MA	02129	SUFFOLK	USA	Child Health and Human Development Extramural Research	002	6	8/19/2022	NON-COMPETING CONTINUATION	$2,946
2022	2017	SPAULDING REHABILITATION HOSPITAL (SRH) VOLUNTEER SERVICES,	300 FIRST AVE	CHARLESTOWN	MA	02129	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	5	6/29/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2018	SPAULDING REHABILITATION HOSPITAL (SRH) VOLUNTEER SERVICES,	300 FIRST AVE	CHARLESTOWN	MA	02129	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	6	9/25/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	SPAULDING REHABILITATION HOSPITAL (SRH) VOLUNTEER SERVICES,	300 FIRST AVE	CHARLESTOWN	MA	02129	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	6	7/1/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $668,514 )
2018	2018	SPAULDING REHABILITATION HOSPITAL (SRH) VOLUNTEER SERVICES,	300 FIRST AVE	CHARLESTOWN	MA	02129	SUFFOLK	USA	Child Health and Human Development Extramural Research	004	6	6/5/2018	NON-COMPETING CONTINUATION	$565,403
2018	2017	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	000	4	1/22/2018	NON-COMPETING CONTINUATION	-$430,137
2018	2017	SPAULDING REHABILITATION HOSPITAL (SRH) VOLUNTEER SERVICES,	300 FIRST AVE	CHARLESTOWN	MA	02129	SUFFOLK	USA	Child Health and Human Development Extramural Research	003	5	2/12/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$122,497
2018	2017	SPAULDING REHABILITATION HOSPITAL (SRH) VOLUNTEER SERVICES,	300 FIRST STREET	CHARLESTOWN	MA	02129	SUFFOLK	USA	Child Health and Human Development Extramural Research	001	5	1/22/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$533,248
2018	2016	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	002	3	2/12/2018	NON-COMPETING CONTINUATION	-$122,497
														Subtotal = $668,514

Issue Date FY: 2017 ( Subtotal = $430,137 )
2017	2017	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	000	4	7/20/2017	NON-COMPETING CONTINUATION	$430,137
														Subtotal = $430,137

Issue Date FY: 2016 ( Subtotal = $423,271 )
2016	2016	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	000	3	6/10/2016	NON-COMPETING CONTINUATION	$423,271
														Subtotal = $423,271

Issue Date FY: 2015 ( Subtotal = $434,034 )
2015	2015	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	001	2	5/20/2015	NON-COMPETING CONTINUATION	$434,034
2015	2014	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	000	1	5/11/2015	NEW	$0
														Subtotal = $434,034

Issue Date FY: 2014 ( Subtotal = $418,092 )
2014	2014	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	000	1	9/9/2014	NEW	$418,092
														Subtotal = $418,092

Grand Total All Awards = $2,374,048

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Mechanisms of intermittent hypoxia-induced motor recovery in persons with SCI

Award Number: R01HD081274

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/10/2014

PERIOD OF PERFORMANCE END DATE: 02/28/2021

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