Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Inhibition of MIF nuclease-mediated parthanatos prevents neuron and oligodendrocyte death in the context of multiple sclerosis

Award Number: F31NS132520
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/04/2023
PERIOD OF PERFORMANCE END DATE: 06/03/2026

Group Awards By:

View Award Description

Inhibition of MIF nuclease-mediated parthanatos prevents neuron and oligodendrocyte death in the context of multiple sclerosis - Project Summary Nearly three million people worldwide are currently living with multiple sclerosis (MS), a complex neurological disease that primarily affects individuals between 20-45 years of age. MS is characterized by peripheral immune cell infiltration into the central nervous system (CNS) with associated reactive gliosis, oligodendrocyte (OL) death, demyelination, and neuroaxonal degeneration. Some of the infiltrates that migrate to the CNS are lymphocytes that target the myelin sheaths of axons. Existing therapies predominately inhibit adaptive immune cells in circulation; however, these medications are often not effective in halting the pathophysiology that underlies progressive CNS degeneration in MS, where immune cell infiltration and activation are minimal. No therapies currently exist to treat this pathology because the molecular mechanisms by which CNS lesions occur in patients with MS is not fully understood. Since disability in progressive MS is driven by the chronic loss of OLs and neurons, this study will investigate the distinct degenerative process of both cell types utilizing relevant models. The ultimate objective of this proposed research is to identify how neurons and OLs die in the context of MS. Understanding this will help identify therapeutic targets to stop these degenerative processes from occurring in patients with MS. For the past decade, our lab has studied a novel, non-apoptotic cell death pathway, parthanatos, that plays an active role in various neurological conditions. Parthanatos-inducing conditions that lead to DNA damage, such as high ROS concentrations, are pathologically prevalent across many neurological diseases including MS. Herein, our lab has created a mouse line with a point mutation that selectively ablates the enzymatic activity of the downstream executioner of parthanatos cell death, macrophage migration inhibitory factor (MIF) nuclease, and synthesized a compound that specifically inhibits MIF nuclease. Both genetic and pharmacologic developments have been shown to mediate protection of dopaminergic neurons in the alpha-synuclein plaque-forming fibril model of Parkinson’s Disease. These experimental tools will be used here to assess the therapeutic efficacy of targeting MIF nuclease in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS and neonatal-derived mouse OLs following exposure to MS-relevant insults. My preliminary data suggest that genetic ablation of MIF nuclease in EAE mice led to decreased neurologic impairment over time. Importantly, genetic ablation of MIF nuclease in EAE mice did not affect peak EAE disease severity or peripheral immune cell infiltration into the spinal cord. I also determined that genetic ablation and pharmacologic inhibition of MIF nuclease in EAE mice protected against retinal ganglion cell and lumbar spinal cord neuron loss. I further revealed that OL precursor cells underwent parthanatos following DNA damage, and that this cell death process was limited by inhibiting upstream parthanatos enzymes in vitro. Therefore, I hypothesize that neurons and OLs die by parthanatos in MS, and that inhibition of MIF nuclease will protect against neuron and OL degeneration in MS-relevant models. Collectively, if neurons and OLs degenerate by parthanatos in MS as indicated by my preliminary data, this proposed research could establish a pharmacological target that can be inhibited to directly mitigate the ongoing loss of grey and white matter in the CNS of patients with this disease.


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 = $33,215 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/9/2025	NON-COMPETING CONTINUATION	$33,215
														Subtotal = $33,215

Issue Date FY: 2025 ( Subtotal = $49,538 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	8/5/2025	NON-COMPETING CONTINUATION	$564
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/27/2024	NON-COMPETING CONTINUATION	$48,974
														Subtotal = $49,538

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/4/2023	NEW	$47,694
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	5/14/2024	NEW	$1,280
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	12/4/2023	NEW	$0
														Subtotal = $48,974

Grand Total All Awards = $131,727

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Inhibition of MIF nuclease-mediated parthanatos prevents neuron and oligodendrocyte death in the context of multiple sclerosis

Award Number: F31NS132520

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/04/2023

PERIOD OF PERFORMANCE END DATE: 06/03/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer