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The impact of mitochondrial and peroxisomal fission dynamics on metabolic signaling during corticogenesis.

Award Number: K00NS125829
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: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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The impact of mitochondrial and peroxisomal fission dynamics on metabolic signaling during corticogenesis. - PROJECT SUMMARY/ABSTRACT Mitochondria are dynamic signaling organelles that constantly undergoes fission (fragmentation) and fusion (elongation) to adapt its structure to the demands of the cell. DRP1 (dynamin-related protein 1) is a GTPase that plays a crucial role in mitochondrial fission. Patients with de novo heterozygous missense mutations in the gene that encodes DRP1, DNM1L, present with neurodevelopmental symptoms. To interrogate the molecular mechanisms by which DRP1 mutations cause neurodevelopmental defects, we are utilizing patient-derived fibroblasts and iPSC-derived models from patients with mutations in different domains of DRP1 who present with clinically disparate conditions. The G32A mutation lies in the GTPase domain of DRP1 and is associated with microcephaly. The R403C mutation lies in the stalk domain of DRP1 and causes progressively severe epilepsy. Specific Aim 1 presents the progress thus far to uncover the impact of DRP1 mutations on mitochondrial structure and metabolic function using patient-derived fibroblasts. Patient cells display elongated mitochondrial structure and impaired coupling efficiency of the electron transport chain (ETC). Specific Aim 2 (the F99 phase of this proposal) will explore the consequences of these findings in neurodevelopment using patient-derived induced pluripotent stem cell (iPSC) models: three-dimensional cerebral organoids and two-dimensional neural progenitor cultures. Confocal imaging and mass cytometry (CyTOF) will be used to determine if patient mutations lead to change of cell fate in early corticogenesis. Further, multi-electrode array (MEA) technology will be leveraged to examine the development of neuronal network activity in patient-derived brain organoids. Understanding the mechanism by which these mutations cause neurological pathology will give insight into the role of mitochondrial dynamics in neurodevelopment. Specific Aim 3 (the K00 phase of this proposal) will develop the applicant into an independent academic researcher investigating the interactions between metabolic signaling and neurodevelopment. The K00 phase will provide the applicant with training in metabolic analysis using carbon tracing and in vitro biochemical assays as well as the professional development and networking necessary to run an independent research laboratory. Overall, the work outlined in this proposal will equip the candidate with both the technical expertise and professional skills to make great strides in the field of metabolism in neurodevelopment.


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: 2025 ( Subtotal = $90,671 )
2025	2025	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/11/2025	NON-COMPETING CONTINUATION	$90,671
														Subtotal = $90,671

Issue Date FY: 2024 ( Subtotal = $86,508 )
2024	2024	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/8/2024	EXTENSION WITH OR WITHOUT FUNDS	$86,508
														Subtotal = $86,508

Grand Total All Awards = $177,179

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The impact of mitochondrial and peroxisomal fission dynamics on metabolic signaling during corticogenesis.

Award Number: K00NS125829

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: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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