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The Molecular Role of C1QL3 and its Binding Partners in Synaptic Regulation

Award Number: F30MH135628
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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The Molecular Role of C1QL3 and its Binding Partners in Synaptic Regulation - PROJECT SUMMARY Neuropsychiatric disorders often cause lifelong disruptions of patients’ lives and lack satisfactory pharmacological interventions. Symptoms in these disorders are likely associated with disruption in synapses resulting from dysfunctional synaptic adhesion molecules (SAM), but the mechanisms by which SAMs may contribute to synaptic dysfunction have not been fully elucidated. Complement C1q like 3 (C1QL3), is a promising SAM for potential therapeutics for neuropsychiatric disorders because it selectively regulates excitatory synapses and may therefore constitute a target for correction of the excitatory/inhibitory synaptic imbalances associated with several neuropsychiatric disorders. To contribute to the future development of novel therapeutics, I will elucidate the molecular mechanisms contributing to C1QL3’s roles in regulating excitatory synapses. My preliminary data suggest that C1QL3 associates with the adhesion G protein-coupled receptor B3 and neuronal pentraxin 1 at synapses in mouse primary neuron cultures, consistent with our previous data suggesting that these proteins promote cell-cell adhesion in heterologous cells in a C1QL3-dependent manner. In Aim 1, I will test whether this hypothesized trans-synaptic adhesion complex truly forms at synapses in neuron cultures, using super resolution microscopy. I will characterize the synaptic nano-architecture of this complex, then determine the extent to which it is dependent on C1QL3 by knocking out C1QL3. I will further elucidate the molecular interactions contributing to trans-synaptic adhesion through structure-function analysis using C1QL3 mutants that are not conducive to complex formation. This will elucidate the specific binding interactions that contribute to C1QL3’s role in promoting synapse architecture and maintenance. In Aim 2, I will study how a novel C1QL3 binding protein contributes to synaptic maintenance, potentially through its interactions with C1QL3. My preliminary data suggest this novel protein increases excitatory synapse density in a C1QL3-dependent manner. I will therefore determine this novel protein’s mechanism of synaptic regulation and the extent to which it modulates the hypothesized C1QL3-mediated trans-synaptic adhesion complex. This study will provide insight into the components of the molecular web of SAMs that regulate synapses and may highlight novel targets for repairing synaptic dysfunction. Through this project I will develop and hone many skills that are essential for my goal of becoming an independent physician-scientist at an academic institution. I am well supported in the M.D./Ph.D. program at UConn Health by my sponsors and clinical mentors that will facilitate the successful completion of this project and development into a promising physician-scientist.


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 = $54,538 )
2025	2025	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Mental Health Research Grants	000	2	6/12/2025	NON-COMPETING CONTINUATION	$54,538
														Subtotal = $54,538

Issue Date FY: 2024 ( Subtotal = $45,419 )
2024	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Mental Health Research Grants	000	1	5/25/2024	NEW	$45,419
2024	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Mental Health Research Grants	001	1	5/25/2024	NEW	$0
														Subtotal = $45,419

Grand Total All Awards = $99,957

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The Molecular Role of C1QL3 and its Binding Partners in Synaptic Regulation

Award Number: F30MH135628

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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