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A p75/Ret Receptor Complex as an Integrator of Survival and Death

Award Number: R01NS089585
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2015
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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A p75/Ret Receptor Complex as an Integrator of Survival and Death - Throughout the developing nervous system excess neurons are generated which are nonessential, or inappropriately connected, and are eliminated by programmed cell death (PCD). In the PNS, the extent of apoptosis is governed by both a limited supply of survival-promoting neurotrophic factors provided by targets of innervation, and by apoptosis-inducing competition factors secreted by “winning neurons” that have successfully competed for these neurotrophic factors. The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are a family of potent growth factors that support the survival of autonomic, somatosensory and spinal motor neurons. The GFLs promote survival and growth through a common signal-transducing receptor tyrosine kinase, Ret. During this grant period we discovered that Ret interacts with p75, a member of the TNF family of death receptors, and p75 enhances GDNF-mediated Ret activation and survival. When p75 is deleted specifically in sensory neurons, approximately 20% are lost between P14 and adulthood, and these losses selectively occur in Ret+ nonpeptidergic nociceptors. These results indicate that p75 is required for the development of the nonpeptidergic nociceptor lineage by fine-tuning Ret-mediated trophic support. We also found that during PCD in sympathetic neurons of the superior cervical ganglion (SCG) Ret is restricted to a subset of degenerating neurons that rapidly undergo apoptosis. Pro-apoptotic conditions induce the association of Ret with p75, thereby enhancing the regulated intramembrane proteolysis (RIP) cleavage of p75 and activation of downstream apoptotic effectors. Deletion of p75 in Ret+ neurons, and deletion of Ret, specifically during PCD, inhibits apoptosis both in vitro and in vivo. These results indicate that Ret acts non-canonically to augment p75-mediated apoptosis. The molecular mechanisms that underlie the ability of p75 to enhance Ret signaling, and for Ret to enhance p75 mediated death, are not well understood, and are the subject of Aim 1. We also discovered recently that semaphorin 3A (Sema3A), a secreted repulsive axon guidance molecule, induces apoptosis of primary SCG neurons, and that deletion of its receptor components, Neuropilin-1 (Npn-1) and PlexinA3 (PA3), significantly reduce PCD in the SCG. Sema3A induces apoptosis via the extrinsic pathway, requiring caspase-8, as opposed to the intrinsic pathway triggered by NGF withdrawal in sympathetic neurons that requires caspase-9. The combination of apoptosis induced by neurotrophic factor deprivation and death receptor activation in the developing SCG raises the question of the extent to which caspase-8 and caspase-9 contribute to apoptosis during PCD, and which death receptors are driving this process. These questions will be the subject of Aim 2. Collectively the experiments proposed here will define the molecular mechanisms and magnitude of the role played by death receptor pathways, such as Npn-1/PA3 and p75, in PCD.


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 = $434,935 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	4/15/2024	NON-COMPETING CONTINUATION	$434,935
														Subtotal = $434,935

Issue Date FY: 2023 ( Subtotal = $448,387 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	4/17/2023	NON-COMPETING CONTINUATION	$448,387
														Subtotal = $448,387

Issue Date FY: 2022 ( Subtotal = $448,387 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	4/22/2022	NON-COMPETING CONTINUATION	$448,387
														Subtotal = $448,387

Issue Date FY: 2021 ( Subtotal = $448,387 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	4/29/2021	NON-COMPETING CONTINUATION	$448,387
2021	2019	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	5/8/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $448,387

Issue Date FY: 2020 ( Subtotal = $448,387 )
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	1/31/2020	COMPETING CONTINUATION	$448,387
2020	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/9/2019	NON-COMPETING CONTINUATION	-$337,764
2020	2019	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	6	2/15/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$33,066
2020	2019	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	12/11/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$337,764
2020	2018	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	2/15/2020	NON-COMPETING CONTINUATION	-$33,066
														Subtotal = $448,387

Issue Date FY: 2019 ( Subtotal = $337,764 )
2019	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/1/2019	NON-COMPETING CONTINUATION	$337,764
														Subtotal = $337,764

Issue Date FY: 2018 ( Subtotal = $337,764 )
2018	2018	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/23/2018	NON-COMPETING CONTINUATION	$33,777
2018	2018	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/19/2018	NON-COMPETING CONTINUATION	$303,987
														Subtotal = $337,764

Issue Date FY: 2017 ( Subtotal = $337,764 )
2017	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	6/6/2017	NON-COMPETING CONTINUATION	$33,777
2017	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/5/2017	NON-COMPETING CONTINUATION	$303,987
														Subtotal = $337,764

Issue Date FY: 2016 ( Subtotal = $337,764 )
2016	2016	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/3/2016	NON-COMPETING CONTINUATION	$337,764
														Subtotal = $337,764

Issue Date FY: 2015 ( Subtotal = $337,944 )
2015	2015	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/6/2015	NEW	$337,944
														Subtotal = $337,944

Grand Total All Awards = $3,917,483

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A p75/Ret Receptor Complex as an Integrator of Survival and Death

Award Number: R01NS089585

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2015

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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