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Bioactivities of pneumococcal cell wall in neuropathogenesis

Award Number: R01AI128756
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/04/2016
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Bioactivities of pneumococcal cell wall in neuropathogenesis - Using the pneumococcus as a model, our lab has revealed many features of the biochemical basis of the inflammatory response to bacteria in the brain. The important discovery of this application is the opening of a new area of pathogenesis at the maternal/fetal interface that will inform newly discovered cell wall/TLR2 effects as a morphogen in the brain. We have determined that cell wall, a universal pathogen associated molecular pattern, circulates in the bloodstream of pregnant mice and traverses the placenta to the fetal brain. The response of fetal neurons is not the well characterized inflammation and neuronal death of the postnatal setting but the exact opposite: neuroproliferation without inflammation. This response involves two new activities of cell wall: 1) induction of cell proliferation via TLR2 without inflammatory signaling, and 2) remodeling of embryonic brain anatomy and changes in postnatal behavior. We will further determine the relevance of these findings to the human brain using organoids. An understanding of the details of this new biology, to be investigated in this application, represents both novel bacterial pathogenesis and an avenue of high potential for tangible medical impact. Using single cell spatial RNASeq and knock out animal models, we propose to identify the signaling cascade initiated by cell wall to modulate brain structure, including determining the links between TLR2/6, the signaling node of the neuronal cilium and the neuronal transcription factor FoxG1. This will connect innate immune receptors to nuclear transcription factors for the first time and define a new activity of TLRs as morphogens. The involvement of the LANDO autophagy pathway will be characterized as a cell wall trafficking/removal pathway associated with defects in cognitive function.


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 = $441,350 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	9	1/21/2025	NON-COMPETING CONTINUATION	$441,350
														Subtotal = $441,350

Issue Date FY: 2024 ( Subtotal = $455,000 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	001	8	5/23/2024	NON-COMPETING CONTINUATION	$45,500
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	8	1/5/2024	NON-COMPETING CONTINUATION	$409,500
														Subtotal = $455,000

Issue Date FY: 2023 ( Subtotal = $455,000 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	7	1/24/2023	NON-COMPETING CONTINUATION	$455,000
														Subtotal = $455,000

Issue Date FY: 2022 ( Subtotal = $455,000 )
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	001	6	2/8/2022	COMPETING CONTINUATION	$455,000
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	003	6	8/30/2022	COMPETING CONTINUATION	$14,554
2022	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	002	5	8/30/2022	NON-COMPETING CONTINUATION	-$14,554
2022	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	5	2/8/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $455,000

Issue Date FY: 2021 ( Subtotal = $448,750 )
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	5	10/23/2020	NON-COMPETING CONTINUATION	$448,750
														Subtotal = $448,750

Issue Date FY: 2020 ( Subtotal = $448,750 )
2020	2020	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	4	11/6/2019	NON-COMPETING CONTINUATION	$448,750
														Subtotal = $448,750

Issue Date FY: 2019 ( Subtotal = $448,750 )
2019	2019	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	3	10/25/2018	NON-COMPETING CONTINUATION	$448,750
														Subtotal = $448,750

Issue Date FY: 2018 ( Subtotal = $448,750 )
2018	2018	ST. JUDE CHILDREN'S RESEARCH HOSPITAL	262 DANNY THOMAS PL MAILSTOP # 509	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	2	10/24/2017	NON-COMPETING CONTINUATION	$448,750
														Subtotal = $448,750

Issue Date FY: 2017 ( Subtotal = $448,750 )
2017	2017	ST. JUDE CHILDREN'S RESEARCH HOSPITAL	262 DANNY THOMAS PL MAILSTOP # 509	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	1	11/4/2016	NEW	$448,750
														Subtotal = $448,750

Grand Total All Awards = $4,050,100

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Bioactivities of pneumococcal cell wall in neuropathogenesis

Award Number: R01AI128756

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 11/04/2016

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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