SYNTHETIC RECONSTRUCTION OF HUMAN CHAPERONE NETWORKS IN YEAST MODELS OF NEURODEGENERATION - PROJECT SUMMARY…

Assistance award details

Assistance award identifier

ASST_NON_R00AG075242_075

FAIN

R00AG075242

Recipient

TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$249,000

Period

Mar 15, 2023 – Apr 30, 2029

Fiscal year

2026

Place of performance state

PA

Source file

FY2026_All_Assistance_Full_20261006.zip

Description

SYNTHETIC RECONSTRUCTION OF HUMAN CHAPERONE NETWORKS IN YEAST MODELS OF NEURODEGENERATION - PROJECT SUMMARY IN AGING NEURONS, THE ACCUMULATION OF KEY MISFOLDED PROTEINS INTO AGGREGATES IS A HALLMARK OF MANY NEURODEGENERATIVE DISEASES. FOR EXAMPLE, PATHOLOGICAL FORMS OF TDP43 BECOME MISLOCALIZED TO THE CYTOPLASM AND ACCUMULATE IN AGGREGATES IN FRONTOTEMPORAL DEMENTIA (FTD) AND OTHER ALZHEIMER DISEASE-RELATED DEMENTIAS (ADRD). HIGHLY INTRICATE NETWORKS OF ENZYMES CALLED MOLECULAR CHAPERONES COMBAT THESE PROCESSES. IN ADRD, IT IS UNKNOWN HOW THE CHAPERONE NETWORKS FAIL AGAINST PATHOLOGICAL FORMS OF ADRD PROTEINS SUCH AS TDP43, FUS, AND TAU. A MAJOR CHALLENGE TO STUDYING CHAPERONE NETWORKS IS THE COMBINATORIAL COMPLEXITY. THE CANONICAL HSP70 NETWORK CONSISTS OF 54 HSP40, 12 HSP70, AND 16 HSP110 GENE VARIANTS, CREATING A LANDSCAPE OF 12,155 POSSIBLE PROTEIN EXPRESSION COMBINATIONS. UNIQUE COMBINATIONS OF THE HSP40-HSP70-HSP110 PROTEINS ARE HYPOTHESIZED TO CONFER SPECIFICITY FOR DIFFERENT MISFOLDED PROTEINS IN THE COMPLEX HUMAN PROTEOME. THIS HYPOTHESIS IS WIDELY ACCEPTED BUT IT HAS NEVER BEEN DIRECTLY TESTED DUE TO TECHNICAL LIMITATIONS. THIS NIH K99/R00 PROPOSAL OUTLINES A PLAN TO DIRECTLY TEST THIS HYPOTHESIS BY BUILDING THE FIRST EXHAUSTIVE MAP OF A CHAPERONE NETWORK AGAINST THE ADRD-ASSOCIATED PROTEINS TDP43, FUS, AND TAU. TO ACHIEVE THIS GOAL, AIM 1 WILL LEVERAGE A NEW GENETIC TECHNIQUE DEVELOPED BY DR. EDWARD BARBIERI TO EXPRESS AND STUDY ALL 12,155 POSSIBLE COMBINATIONS OF THE HUMAN HSP40-HSP70-HSP110 NETWORK IN YEAST MODELS OF ADRD. THE CHAPERONES IDENTIFIED AS HAVING ACTIVITY AGAINST TDP43 IN YEAST WILL BE FURTHER STUDIED IN AIM 2 USING HUMAN CELLS AND IN VITRO ASSAYS. WITH HUMAN CELL MODELS, DR. BARBIERI WILL STUDY THE EFFECT OF THE TDP43-ACTIVE CHAPERONES ON CYTOPLASMIC TDP43 AGGREGATION AND ASSESS IF THE CHAPERONES RESTORE NATIVE TDP43 FUNCTION IN MRNA SPLICING IN BOTH HEK-293T CELLS AND NEURONS. USING IN VITRO BIOCHEMISTRY, HE WILL MEASURE CHAPERONE ACTIVITY