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Regulation of lysosomal potassium channels

Award Number: R01GM133172
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Regulation of lysosomal potassium channels - Program Director/Principal Investigator (Last, First, Middle): Ren, Dejian The major goal of the proposed research is to understand how the ion channel TMEM175 we discovered controls lysosomal function and regulates neurodegenerative diseases. Lysosomes are uniquely important for many functions such as material digestion, recycling, cellular clearance, exocytosis, wound repair, Ca2+ signaling, nutrient sensing. They are also the platform for signaling networks involving the mTOR and AKT kinases and transcription factor TFEB. Lysosomal dysfunctions are implicated in numerous diseases such as lysosomal storage and neural degenerative diseases, and is a hallmark of aging. Despite the importance, their biophysical properties have been poorly defined, and there are several “controversies” even in processes as basic as acidification. We have recently started to fill the knowledge gap by using organelle electrophysiology, channel protein discovery and functional studies in mice and human. In the past period, we have focused on the TMEM175 protein that we discovered to form the K+ channel we first recorded. TMEM175 is a major locus linked to several neurodegenerative diseases including Parkinson's disease (PD) and Lewy body dementia. We found that TMEM175 is important for the acidification of lysosomes. TMEM175 knockout (KO) neurons are prone to stress-induced damages and have accelerated spreading of misfolded α-synuclein. KO mice lose dopaminergic neurons, a hallmark of PD. We also found that a PD-associated variations affect lysosomal ion channel function and modulate Parkinson's disease pathology. Thus, TMEM175 is important for lysosomal function and neuronal fitness, and bidirectionally regulates neurodegenerative diseases. We propose to further reveal how TMEM175 is activated by the kinase protein AKT (Aim 1), how the channel contributes to lysosomal function such as acidification (Aim 2) and how its genetic variations contribute to variations in neuronal function and neurological diseases (Aim 2). As TMEM175 is implicated in PD and several other neurodegenerative diseases, the work will also reveal how genetic variations contribute to functional variations of lysosomes and neuronal fitness, and will provide foundation for the intervention of neural degeneration diseases. Page


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 = $349,375 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	6	4/2/2026	NON-COMPETING CONTINUATION	$349,375
														Subtotal = $349,375

Issue Date FY: 2025 ( Subtotal = $349,375 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	5	4/7/2025	COMPETING CONTINUATION	$349,375
2025	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	4	6/25/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $349,375

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	4	3/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $325,837 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	4	3/14/2022	NON-COMPETING CONTINUATION	$293,250
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	4	6/9/2022	NON-COMPETING CONTINUATION	$32,587
														Subtotal = $325,837

Issue Date FY: 2021 ( Subtotal = $325,837 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	3	6/14/2021	NON-COMPETING CONTINUATION	$325,837
														Subtotal = $325,837

Issue Date FY: 2020 ( Subtotal = $325,837 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	2	4/16/2020	NON-COMPETING CONTINUATION	$325,837
														Subtotal = $325,837

Issue Date FY: 2019 ( Subtotal = $333,174 )
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	3/27/2019	NEW	$333,174
														Subtotal = $333,174

Grand Total All Awards = $2,009,435

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Regulation of lysosomal potassium channels

Award Number: R01GM133172

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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