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Elucidating the molecular drivers of impaired mobility within and outside the CNS in Alzheimer?s disease and related disorders

Award Number: R01AG059732
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Responding to PAR 17-029: Dynamic Interactions between systemic or non-neuronal systems and the brain in aging and in AD, this study will identify the molecular mechanisms driving impaired mobility, an understudied aging and AD phenotype, as highlighted by NIA workshops, Aging, the CNS, and Mobility. AD and other brain pathologies are related to impaired mobility in older adults with and without dementia, but do not fully explain impaired mobility. These pathologies extend beyond the brain to spinal cord, but even accounting for these pathologies does not fully explain mobility and the molecular drivers of these pathologies are unknown. This suggests that there are also drivers without a pathologic footprint that remain unidentified in these tissues. Mobility derives from interacting subsystems that extend beyond the brain to spinal cord and muscle. Therefore, this postmortem study in older adults will identify molecular drivers (genes and their proteins) of impaired mobility in key mobility tissues controlling for the presence of AD and other CNS pathologies. This study will leverage clinical and postmortem resources from older participants of the Rush Memory and Aging Project (R01AG17917). Our systems biology approach will be applied to new gene expression data obtained from key mobility tissues in brain, spinal cord and muscle (Aim1). Tissues will come from the same persons, all of whom had instrumented gait testing with a wearable sensor proximate to death. In each tissue, we will identify mobility-related molecular systems controlling for CNS pathologies (Aim2). Causal network inference will be used to nominate influential genes controlling these systems (Aim3). Validating protein levels of influential genes within and across these tissues will yield a high-confidence list of genes driving impaired mobility (Aim4). Compelling pilot studies support this proposal. 1) Combinations of wearable sensor mobility metrics are more specific for AD dementia than conventional gait speed. 2) AD and other pathologies extend to spinal cord and are related to mobility, emphasizing the need to identify drivers of these pathologies in motor tissues outside the brain. 3) Also, the limited explanatory power of CNS pathologies for mobility highlights the need to identify molecular drivers of impaired mobility in key motor tissues that may not have a known pathologic footprint. 4) High quality genome-wide transcriptomic data extracted from key motor tissues show differentially expressed genes are related to gait, cognition and AD pathology. 5) Applying the system biology methods to a cortical cognitive gene network, followed by validation with protein, we identified cortical proteins driving cognition. Leveraging broad expertise, this study will provide an in-depth description of the molecular drivers within interconnected subsystems underlying mobility within and outside the CNS. Validating influential genes provides a means to move beyond a descriptive study by providing novel therapeutic targets. This study has potential to make a sustained impact on aging research, inform on efforts to maintain ambulation and reduce a major adverse health consequence of aging and AD.


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: 2023 ( Subtotal = $663,310 )
2023	2023	RUSH UNIVERSITY MEDICAL CENTER	1620 W HARRISON ST	CHICAGO	IL	60612	COOK	USA	Aging Research	000	5	3/7/2023	NON-COMPETING CONTINUATION	$663,310
														Subtotal = $663,310

Issue Date FY: 2022 ( Subtotal = $697,563 )
2022	2022	RUSH UNIVERSITY MEDICAL CENTER	1620 W HARRISON ST	CHICAGO	IL	60612	COOK	USA	Aging Research	000	4	4/25/2022	NON-COMPETING CONTINUATION	$697,563
														Subtotal = $697,563

Issue Date FY: 2021 ( Subtotal = $46,314 )
2021	2021	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PRKWY	CHICAGO	IL	60612	COOK	USA	Aging Research	001	3	4/28/2021	NON-COMPETING CONTINUATION	-$694,393
2021	2021	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PRKWY	CHICAGO	IL	60612	COOK	USA	Aging Research	000	3	3/18/2021	NON-COMPETING CONTINUATION	$740,707
														Subtotal = $46,314

Issue Date FY: 2020 ( Subtotal = $1,405,734 )
2020	2020	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PRKWY	CHICAGO	IL	60612	COOK	USA	Aging Research	001	2	3/31/2020	NON-COMPETING CONTINUATION	$711,340
2020	2019	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PRKWY	CHICAGO	IL	60612	COOK	USA	Aging Research	000	1	1/11/2020	NEW	$694,394
														Subtotal = $1,405,734

Issue Date FY: 2019 ( Subtotal = $711,340 )
2019	2019	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PRKWY	CHICAGO	IL	60612	COOK	USA	Aging Research	000	1	4/23/2019	NEW	$711,340
														Subtotal = $711,340

Grand Total All Awards = $3,524,261

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Elucidating the molecular drivers of impaired mobility within and outside the CNS in Alzheimer?s disease and related disorders

Award Number: R01AG059732

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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