Friday, April 19, 2024 4/19/2024

Molecular mechanisms underlying mitochondria-lysosome membrane contact sites in neuronal function and neurodegeneration

Award Number: R00NS109252
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Both mitochondria and lysosomes are critical for regulating neuronal metabolism and function, and dysfunction of both organelles has been implicated in multiple neurodegenerative diseases including Parkinson’s and Charcot-Marie-Tooth (CMT) disease. However, the interplay between these two organelles in regulating neuronal homeostasis and driving neurodegeneration are still not well understood. Inter-organelle membrane contacts form between two different organelles and are critical sites for mediating organelle dynamics, metabolite exchange and signaling, but whether mitochondria and lysosomes form similar membrane contact sites to regulate their functional crosstalk was previously unknown. I recently identified the formation and regulation of mitochondria-lysosome membrane contact sites which represent a new pathway for the bidirectional regulation of mitochondria and lysosomes, but the role of these contact sites in neurons has not yet been explored. Importantly, further elucidating the neuronal role of mitochondria-lysosome contacts provides important insight into coupled mitochondrial and lysosomal function in neurons and potential pathways for their coupled dysfunction in multiple neurodegenerative diseases. In this project, I propose to investigate the molecular mechanisms underlying mitochondria-lysosome contact function in healthy and diseased neurons during both the K99 and R00 phases using long-term cultures of human induced pluripotent stem cell (iPSC)-derived neurons grown on micropatterned substrates to facilitate organelle imaging via advanced microscopy techniques including super-resolution imaging, electron microscopy and high spatial and temporal resolution live cell microscopy. In Aim 1, I will investigate how mitochondria-lysosome contacts regulate neuronal health and homeostasis by examining 1) the bidirectional relationship between mitochondrial trafficking and mitochondria-lysosome contacts in axons, and 2) the role of contacts in regulating calcium and lipid dynamics and exchange between mitochondria and lysosomes in neurons. Moreover, as lysosomal Rab7 GTP hydrolysis from GTP-bound state to GDP-bound state driven by a mitochondrial GAP (GTPase activating protein) regulates mitochondria-lysosome contact dynamics, disruption of Rab7 may contribute to neurodegeneration by misregulating contact dynamics and downstream lysosomal and mitochondrial function. In Aim 2, I will investigate the role of Rab7-mediated mitochondria-lysosome contact misregulation in the neurodegeneration of two diseases genetically and functionally linked to both mitochondrial and lysosomal dysfunction: 1) Parkinson’s disease in which various familial genes disrupt Rab7 GTP state, and 2) CMT as autosomal dominant mutations in Rab7 result in CMT Type 2B. Together, the proposed research and career plan offers important new training in experimental techniques and disease modeling, which are essential for my transition to independence and for ultimately achieving my long-term goal of uncovering cellular mechanisms underlying disease pathogenesis at the intersection of inter-organelle contacts andneurodegeneration.


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 = $0 )
2024	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $253,667 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	1/12/2023	SUPPLEMENT FOR EXPANSION	$4,667
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	3/30/2023	NON-COMPETING CONTINUATION	$24,900
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/23/2022	NON-COMPETING CONTINUATION	$224,100
														Subtotal = $253,667

Issue Date FY: 2022 ( Subtotal = $348,824 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	4	4/1/2022	NON-COMPETING CONTINUATION	$17,469
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	12/31/2021	SUPPLEMENT FOR EXPANSION	$43,691
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/1/2021	NON-COMPETING CONTINUATION	$231,531
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	4	3/4/2022	SUPPLEMENT FOR EXPANSION	$56,133
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	12/6/2021	NON-COMPETING CONTINUATION	$0
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	1/11/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $348,824

Issue Date FY: 2021 ( Subtotal = $31,610 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	7/16/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	7/12/2021	SUPPLEMENT FOR EXPANSION	$31,065
2021	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/26/2021	EXTENSION WITH OR WITHOUT FUNDS	$545
														Subtotal = $31,610

Issue Date FY: 2020 ( Subtotal = $249,000 )
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	9/21/2020	EXTENSION WITH OR WITHOUT FUNDS	$249,000
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	9/24/2020	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $249,000

Grand Total All Awards = $883,101

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Molecular mechanisms underlying mitochondria-lysosome membrane contact sites in neuronal function and neurodegeneration

Award Number: R00NS109252

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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