ASC OLIGOMERIZATION AND TRANSMISSION AS AN INITIATING EVENT FOR PROTEIN AGGREGATION IN SYNUCLEINOPATHY DEME…
Federal financial assistance recorded from USAspending. This is not a procurement contract.
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ASST_NON_R00AG066862_075 · CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE W… · Department of Health and Human Services
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- Assistance award identifier
- ASST_NON_R00AG066862_075
- FAIN
- R00AG066862
- Recipient
- CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY
- Awarding agency
- Department of Health and Human Services
- Funding agency
- Department of Health and Human Services
- Assistance listing (CFDA)
- 93.866
- Total obligated
- $790,462
- Period
- Sep 1, 2022 – Aug 31, 2025
- Fiscal year
- 2022
- Place of performance state
- OH
- Source file
- FY2022_All_Assistance_Full_20261006.zip
Description
ASC OLIGOMERIZATION AND TRANSMISSION AS AN INITIATING EVENT FOR PROTEIN AGGREGATION IN SYNUCLEINOPATHY DEMENTIAS - SYNUCLEINOPATHY DEMENTIAS (SYN-ÂDEMENTIAS) ARE AGE RELATED, PROGRESSIVE NEURODEGENERATIVE DISEASES THAT ARE CHARACTERIZED BY A-ÂSYNUCLEIN (ASYN) RICH NEURONAL INCLUSIONS CALLED LEWY BODIES (LBS). SYN-ÂDEMENTIAS INCLUDE DEMENTIA WITH LEWY BODIES (DLB), PARKINSONâS DISEASE WITH DEMENTIA (PDD), AS WELL AS A SUBSET OF ALZHEIMERâS DISEASE (AD) CASES WITH LB PATHOLOGY WHICH CONSTITUTE ~40% OF AD CASES. SUSTAINED NEUROINFLAMMATION (MEDIATED PRIMARILY BY MICROGLIA) AND PROGRESSIVE ASYN AGGREGATION ARE HALLMARKS OF SYN-Â DEMENTIAS. WE RECENTLY DESCRIBED THE ACTIVATION OF THE NOD LIKE RECEPTOR PROTEIN-Â3 (NLRP3) INFLAMMASOME IN MOUSE SYNUCLEINOPATHY MODELS AND IN HUMAN PD BRAINS. THE NLRP3 INFLAMMASOME IS A MULTI-ÂPROTEIN ARM OF THE INNATE IMMUNE SYSTEM WHICH, WHEN ACTIVATED, RESULTS IN THE PRODUCTION OF THE CYTOKINE INTERLEUKIN-Â1 BETA (IL-Â 1SS), AS WELL AS OLIGOMERIZED APOPTOSIS-ÂASSOCIATED SPECK-ÂLIKE PROTEIN CONTAINING A CASPASE RECRUITMENT DOMAIN (ASC), WHICH IS THE ADAPTOR PROTEIN OF THE NLRP3 INFLAMMASOME. IT IS CURRENTLY UNKNOWN WHAT PATHOLOGICAL ROLE INFLAMMASOME ACTIVATION MAY PLAY IN THE PROGRESSION OF SYN-ÂDEMENTIAS. OUR PRELIMINARY DATA SUGGESTS THAT MICROGLIA-ÂRELEASED ASC MAY BE TAKEN UP BY NEURONS AND MAY CROSS-ÂSEED ASYN FIBRILIZATION. THE OVERARCHING GOAL OF THIS PROPOSAL IS TO ELUCIDATE THE PATHOLOGICAL ROLE OF MICROGLIA TO NEURON TRANSMISSION OF OLIGOMERIZED ASC IN CONTRIBUTING TO PROGRESSIVE ASYN AGGREGATION IN SYN-ÂDEMENTIAS. WE ALSO SEEK TO ELUCIDATE THE SIGNALING MECHANISMS IN MICROGLIA THAT LEAD TO THE OLIGOMERIZATION AND RELEASE OF ASC, AND THE MECHANISMS IN NEURONS THAT LEAD TO ITS UPTAKE. IN AIM 1, I WILL PERFORM A SERIES OF EXPERIMENTS INCLUDING PROTEIN MISFOLDING CYCLIC AMPLIFICATION (PMCA) AND NEURON/MICROGLIA CO-ÂCULTURE STUDIES IN MICROFLUIDIC CHAMBERS TO SUPPORT OUR PRELIMINARY FINDINGS. THESE E