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Identifying Pathophysiological Signatures of DLB Cognitive and Neuropsychiatric Decline Using a Systems-Based Proteomic Approach

Award Number: K23NS119964
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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Identifying Pathophysiological Signatures of DLB Cognitive and Neuropsychiatric Decline Using a Systems-Based Proteomic Approach - Project Summary / Abstract Dr. Higginbotham is a promising physician-scientist who aspires to unravel the molecular pathophysiology underlying the cognitive and neuropsychiatric decline of Dementia with Lewy bodies (DLB) and identify novel protein signatures that help monitor and treat these debilitating symptoms. This K23 will advance her goals by providing training and mentorship in the following core competencies: 1) bioinformatics; 2) molecular proteomic techniques; and 3) clinical observational research. Dr. Higginbotham has assembled a mentoring team with unparalleled expertise in these areas and their applications to neurodegeneration research. Her primary mentor, Dr. Allan Levey, is a world-renowned cognitive neurologist who leads a highly productive laboratory with basic and translational expertise in Alzheimer's disease (AD) research. Her co-mentor, Dr. Nicholas Seyfried, is an expert in mass spectrometry (MS)-based proteomics and Director of the Emory Integrated Proteomics Core. She will also work closely with a host of collaborators who will provide key biospecimen and analytical resources. This project will use a systems-based proteomics approach to globally profile the corticolimbic pathophysiology of DLB and identify protein signatures of this dysfunction in cerebrospinal fluid (CSF). The rationale for these experiments stems from a staggering lack of biomarkers that assist in the monitoring and treatment of DLB cognitive and neuropsychiatric decline. While synuclein accumulation in corticolimbic regions correlates strongly to these devastating non-motor symptoms, little is known regarding the complex molecular processes surrounding this pathology. Therefore, efforts to better define the corticolimbic pathophysiology of DLB promise to not only enhance our scientific understanding of disease, but also promote the discovery of novel molecular signatures that advance the clinical management of its cognitive and neuropsychiatric decline. Dr. Higginbotham has spent the last two years optimizing brain-CSF integrative proteomic strategies in AD. This work resulted in the identification of novel CSF AD protein signatures linked to a diverse range of cortical pathophysiology. These exciting analyses comprise much of the pilot data for this proposal and will serve as a template for its experiments in DLB. In Aim 1, Dr. Higginbotham will apply co- expression network analysis to the DLB corticolimbic proteome to identify key disease-associated pathways. She will then use co-immunoprecipitation MS to examine pathological synuclein interactors in disease. In Aim 3, she will measure protein signatures of this brain-based pathophysiology in DLB CSF. Based on preliminary data, Dr. Higginbotham hypothesizes that the cortical and limbic regions of the DLB brain feature altered protein pathways and synuclein interactors involved in cellular metabolism. She also expects this corticolimbic pathophysiology to manifest in the CSF as unique DLB protein signatures that could advance our ability to monitor and treat its cognitive and neuropsychiatric decline. This work will prepare Dr. Higginbotham to compete for R01 funding in novel mechanistic and biomarker research in DLB and related parkinsonian disorders.


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 = $195,156 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/13/2025	NON-COMPETING CONTINUATION	$195,156
														Subtotal = $195,156

Issue Date FY: 2024 ( Subtotal = $195,156 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/1/2024	NON-COMPETING CONTINUATION	$195,156
														Subtotal = $195,156

Issue Date FY: 2023 ( Subtotal = $195,156 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/22/2023	NON-COMPETING CONTINUATION	$195,156
														Subtotal = $195,156

Issue Date FY: 2022 ( Subtotal = $195,156 )
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/24/2022	NEW	$195,156
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	3/14/2022	NEW	$0
														Subtotal = $195,156

Grand Total All Awards = $780,624

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Identifying Pathophysiological Signatures of DLB Cognitive and Neuropsychiatric Decline Using a Systems-Based Proteomic Approach

Award Number: K23NS119964

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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