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Identification of enteric Juvenile Protective Factors and their role in stimulating neurogenesis in the adult and ageing Enteric Nervous System

Award Number: R01AG066768
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Intestinal motility is regulated by the Enteric Nervous System (ENS), which resides entirely within the gut wall and comprises the largest collection of neurons and glial cells outside of the brain. Previously, we have provided evidence that post-natal development and adult maintenance of the ENS are controlled by distinct fetal-juvenile Sox10-expressing and adult Nestin-expressing Enteric Neural Stem Cells (ENSC). With maturation, the Sox10-expressing cells lose their neurogenic potential in healthy gut but regain it after specific types of injuries, suggesting that certain juvenile protective factors (JPFs) that allow for Sox10+ cells to generate neurons in juvenile gut are lost in adults, but are re-introduced upon injury in adults. The continual genesis of neurons throughout life suggests that a consistent loss of neurons during the juvenile or adult life is due to significant insufficiencies in the neurogenic capacity of ENSC active at that time. Aging is associated with significant loss of enteric neurons and associated chronic intestinal dysmotility, suggesting that an insufficiency in neurogenic capacity of adult ENSC is responsible for such disorders and that the key to crafting a long-term cure for the elderly patients rests in finding novel strategies to increase or supplement existing adult neurogenesis to normalize ENS structure and function. If latent neurogenic capacity of adult Sox10+ cells can be modulated by JPFs, we hypothesize that identifying, recruiting, and re-introducing JPFs into the aging gut would restart neurogenesis from the newly re-invigorated Sox10+ ENSC and that this strategy holds promise for providing lasting relief to elderly suffering from chronic intestinal dysmotility by supplementing insufficient adult Nestin+ derived enteric neurogenesis. Here, we provide significant preliminary data that identifies some putative extrinsic and intrinsic JPFs and test their effect on ENSC behavior and in this proposal, we aim to use next-generation sequencing, large-scale single-cell measurements, integrative cross-platform analyses, and cutting-edge computational tools to identify diverse putative JPFs, describe the regulatory networks through which they act, and functionally validate their ability to modulate neurogenic capacity using our novel biological insight to correct ENS structure and function in animal models of aging.


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 = $583,459 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Aging Research	000	4	12/12/2023	NON-COMPETING CONTINUATION	$583,459
														Subtotal = $583,459

Issue Date FY: 2023 ( Subtotal = $656,204 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Aging Research	000	3	1/5/2023	NON-COMPETING CONTINUATION	$656,204
														Subtotal = $656,204

Issue Date FY: 2022 ( Subtotal = $663,844 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Aging Research	001	2	5/3/2022	NON-COMPETING CONTINUATION	$66,385
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Aging Research	000	2	12/6/2021	NON-COMPETING CONTINUATION	$597,459
														Subtotal = $663,844

Issue Date FY: 2021 ( Subtotal = $660,586 )
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Aging Research	000	1	1/4/2021	NEW	$660,586
														Subtotal = $660,586

Grand Total All Awards = $2,564,093

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Identification of enteric Juvenile Protective Factors and their role in stimulating neurogenesis in the adult and ageing Enteric Nervous System

Award Number: R01AG066768

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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