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Establishing the Function of TMEM184B in mTORC1 Regulation and Synaptic Maintenance

Award Number: R01NS105680
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: 07/01/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Establishing the Function of TMEM184B in mTORC1 Regulation and Synaptic Maintenance - Synaptic disruption is a prelude to and often a primary cause of neurological disease, but we have few strategies to correct dysmorphic synapses, even if they occur early in the degenerative process. Growth control pathways, i.e. those that promote protein and lipid synthesis while reducing catabolism, regulate synaptic form that in turn ensures efficient function and plasticity. The 7-pass endosomal membrane protein TMEM184B regulates synaptic structure and function across species; accordingly, its loss causes exuberant synaptic sprouting, swollen nerve terminals, and altered excitability. In humans, disruption of conserved amino acids in TMEM184B is linked to nervous system disruptions including microcephaly, intellectual disability, corpus callosum hypoplasia, and epilepsy. While TMEM184B genetic disruptions are rare, the disorders produced by TMEM184B disruption are common, suggesting an intersection with key neurological pathways. Our long-term goal is to define the mechanisms underlying TMEM184B variant-associated nervous system disorders in order to provide mechanistic guidance for their treatment. Our overall objectives in this proposal are to determine how TMEM184B directs key signaling pathways supporting neuronal structure and function and to illuminate how patient variants of TMEM184B alter synaptic transmission and resultant behavior. TMEM184B has sequence similarity to bile acid and sterol transporters, but this proposed molecular function remains untested. Preliminary data and published studies suggest an intersection between TMEM184B and mTOR, but how TMEM184B influences mTOR pathway activity is completely unknown. We hypothesize that TMEM184B is an endosomal transporter whose function impacts mTORC1 signaling to promote synaptic structure and function. In Aim1, we will evaluate the specific contributions of TMEM184B to the mTORC1 pathway using primary cortical neuron cultures from wild type and TMEM184B mutant mice. We will evaluate the function of upstream activators and downstream effectors of mTORC1 using functional readouts as well as lipidomic and phospho-proteomic tools. In Aim 2, we will model human disease-linked TMEM184B variants in Drosophila by introducing patient mutations into conserved amino acids. With these flies we will evaluate synaptic form, function (electrophysiological recording), and behavior. In Aim 3, we will establish the molecular function of the TMEM184B protein using a combination of in silico, thermodynamic, and proteomic assays to reveal candidate transport substrates and other metabolites most affected by TMEM184B disruption. Overall, our multifaced approach will illuminate the mechanism through which TMEM184B acts to ensure synaptic morphology and function while enabling a better classification of TMEM184B-associated disorders with others of similar etiology, facilitating improved diagnosis and treatment.


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: 2026 ( Subtotal = $398,827 )
2026	2026	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	5/19/2026	NON-COMPETING CONTINUATION	$398,827
														Subtotal = $398,827

Issue Date FY: 2025 ( Subtotal = $389,148 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	12/5/2024	NON-COMPETING CONTINUATION	$389,148
2025	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	5/30/2025	COMPETING CONTINUATION	$0
2025	2022	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/2/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $389,148

Issue Date FY: 2024 ( Subtotal = $434,584 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	11/27/2023	COMPETING CONTINUATION	$434,584
2024	2022	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/20/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $434,584

Issue Date FY: 2022 ( Subtotal = $351,833 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/18/2022	NON-COMPETING CONTINUATION	$351,833
														Subtotal = $351,833

Issue Date FY: 2021 ( Subtotal = $369,393 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/5/2021	NON-COMPETING CONTINUATION	$369,393
														Subtotal = $369,393

Issue Date FY: 2020 ( Subtotal = $376,519 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/20/2020	NON-COMPETING CONTINUATION	$376,519
														Subtotal = $376,519

Issue Date FY: 2019 ( Subtotal = $361,964 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/19/2019	NON-COMPETING CONTINUATION	$361,964
														Subtotal = $361,964

Issue Date FY: 2018 ( Subtotal = $733,306 )
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/18/2018	SUPPLEMENT FOR EXPANSION	$366,911
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/9/2018	NEW	$366,395
														Subtotal = $733,306

Grand Total All Awards = $3,415,574

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Establishing the Function of TMEM184B in mTORC1 Regulation and Synaptic Maintenance

Award Number: R01NS105680

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: 07/01/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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