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Retooling innate immunity: An investigation of TLR-mediated glial priming across lifespan

Award Number: R01NS120689
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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This proposal examines how a novel TLR glial signaling pathway drives phagocytic competence in glia, and defines its function in pruning neuronal number and connectivity across lifespan. Glia provide an extensive support system for healthy neurons by promoting their survival, connectivity, and synaptic function. Remarkably, glia can rapidly switch roles to precisely eliminate dying neurons or unwanted neurites/synapses by phagocytosis. These diametrically opposed functions necessitate fail-safe signaling mechanisms between neurons and glia; yet hese crucial regulatory mechanisms have remained largely obscure. Toll-like receptor (TLR) pathways were first identified for their roles in embryonic patterning and have since been defined as a conserved centerpiece of innate immunity. Our lab made the unexpected discovery that one of the most pronounced phenotypes associated with loss of a Drosophila TLR, a dramatic increase in the number of apoptotic neurons during development, is caused by selective loss of the TLR in glia. We demonstrated that release of the TLR ligand from dying neurons activates a novel TLR pathway in glia to drive phagocytic competence. In this proposal we build on our novel preliminary findings to establish how this pathway regulates the speed and specificity of debris clearance, and define its roles in neuron-glia interactions in synapse, neurite, and neuron removal across lifespan. Our unifying hypothesis is that non-canonical TLR signaling underlies the speed and specificity of debris clearance critical for proper CNS development and function. In the first aim, we focus on elucidating how glia are transformed into phagocytes during development by defining how information is relayed through the TLR pathway to elucidate how glia are primed to become phagocytic. In the second aim, we seek to extend our published work to investigate whether TLR signaling is a widespread early detection system to alert glia to the presence of neuronal debris. And in the third aim, we examine the function of TLR signaling in sculpting circuits in the olfactory system based on our preliminary findings that glial TLR signaling constrains synapse number in this well defined circuit. Here we propose to leverage the fly olfactory circuit as a model for defining glial phagocytic function in synapse maintenance. Together, these studies will shed critical light on the early signaling interactions between glia and their phagocytic substrates essential for brain health across lifespan.


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 = $362,250 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/14/2023	NON-COMPETING CONTINUATION	$362,250
														Subtotal = $362,250

Issue Date FY: 2023 ( Subtotal = $402,500 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	1/30/2023	NON-COMPETING CONTINUATION	$40,250
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/17/2023	NON-COMPETING CONTINUATION	$362,250
														Subtotal = $402,500

Issue Date FY: 2022 ( Subtotal = $402,500 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/24/2022	NON-COMPETING CONTINUATION	$40,250
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/2/2021	NON-COMPETING CONTINUATION	$362,250
														Subtotal = $402,500

Issue Date FY: 2021 ( Subtotal = $402,500 )
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/18/2020	NEW	$402,500
														Subtotal = $402,500

Grand Total All Awards = $1,569,750

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Retooling innate immunity: An investigation of TLR-mediated glial priming across lifespan

Award Number: R01NS120689

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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