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Understanding the mechanisms behind complement mediated synapse elimination in neuroinflammatory disease

Award Number: F30AI197455
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Understanding the mechanisms behind complement mediated synapse elimination in neuroinflammatory disease - Project Summary/Abstract The goal of this proposal is to understand how the complement component C1q impacts multiple sclerosis (MS)-related neuroinflammatory disease, and to develop a novel strategy to target complement therapeutically. MS is a neurological disease with an increasing health burden in the US. Despite significant improvements in therapy to treat episodic inflammation in relapsing-remitting disease, many MS patients develop a progressive neurodegenerative disease characterized by significant synapse loss, axon degeneration and brain atrophy with no effective treatments available. This is largely because the mechanisms behind how neurodegeneration is initiated and propagated in progressive MS patients remain poorly understood. Our lab has shown in MS patient tissue, a marmoset model of MS, and a mouse model of MS, (Experimental Autoimmune Encephalitis, EAE) that synapse loss occurs in the visual thalamus via microglia which engulf synaptic proteins. In the thalamus, we also showed an increase in complement proteins C1q and C3, which are known to regulate synapse elimination in development and disease. Interestingly, only C3 localized to the synapses. This was particularly intriguing given that C1q is typically upstream of C3 and would also be expected to localize to the synapse. We have since shown that microglia surrounding chronic active lesions in MS patients are particularly high in C1q. We have also demonstrated that with microglia-specific C1q ablation in the mouse EAE model, microglia decrease expression of Clec7a, which is a marker of reactive microgliosis, and they adopt a more branched, homeostatic morphology. These findings suggest that C1q plays an important role in regulating the reactive state of microglia and beg a further understanding of its role in regulating microglial inflammatory signaling. I hypothesize that microglia-derived C1q triggers microglia to develop into a pro-inflammatory state, which is important for both propagating neuroinflammation and for inducing astrocytes to secrete C3 necessary for synapse loss. To answer these questions, I have acquired powerful in vivo molecular genetic tools to evaluate the role of C1q in regulating neuroinflammation and C3 production necessary for synapse loss (Aim 1). I will then assess whether knocking down C1q and C3 expression with antisense oligonucleotides (ASOs) will rescue synapses and attenuate both reactive gliosis and neuroinflammation (Aim 2). These aims will be accomplished under the guidance of my sponsor Dr. Schafer (expert in microglial complement biology and neuroinflammation) and co-sponsor Dr. Ram (clinician and expert in the complement system), where I will receive critical training in neuroinflammation, complement biology, microscopy, and transcriptomics. I will also receive training in the use of ASOs from my collaborator Dr. Watts. These studies will advance our understanding of how the complement system influences neuroinflammation and synapse loss with high therapeutic potential. In the process, I will also receive a strong foundation to support my future career as a physician scientist with a focus in neuroimmunology.


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 = $34,848 )
2026	2026	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	001	1	4/22/2026	NEW	$0
2026	2026	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	1	4/22/2026	NEW	$34,848
														Subtotal = $34,848

Grand Total All Awards = $34,848

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Understanding the mechanisms behind complement mediated synapse elimination in neuroinflammatory disease

Award Number: F30AI197455

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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