ROLE OF HEPARAN SULFATE IN NEURAL CELL VULNERABILITY TO PRIONS - PROJECT SUMMARY / ABSTRACT A MAJOR UNRESOL…

Assistance award details

Assistance award identifier

ASST_NON_R00AG061251_075

FAIN

R00AG061251

Recipient

UNIVERSITY OF ALABAMA AT BIRMINGHAM

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$747,000

Period

Aug 15, 2022 – Jul 31, 2025

Fiscal year

2022

Place of performance state

AL

Source file

FY2022_All_Assistance_Full_20261006.zip

Description

ROLE OF HEPARAN SULFATE IN NEURAL CELL VULNERABILITY TO PRIONS - PROJECT SUMMARY / ABSTRACT A MAJOR UNRESOLVED QUESTION IN NEURODEGENERATIVE DISEASE IS THE MECHANISMS THAT DRIVE SELECTIVE CELL VULNERABILITY. HEPARAN SULFATE PROTEOGLYCANS (HSPGS) ARE GLYCOPROTEINS THAT PROMOTE OLIGOMERIZATION OF AMYLOID- SS AND PRIONS IN VITRO AND SLOW THE CLEARANCE OF AMYLOID-SS IN THE BRAIN OF AN ALZHEIMER’S DISEASE MOUSE MODEL. HSPGS INTERACT WITH MISFOLDED PROTEINS THROUGH THEIR HS CHAINS AND PROMOTE THEIR INTERNALIZATION IN IMMORTALIZED NEURAL CELLS. THIS PROTEIN AGGREGATE UPTAKE IS PROFOUNDLY IMPACTED BY THE HS LENGTH AND LEVEL OF SULFATION WHICH, IMPORTANTLY, BROADLY DIFFER BETWEEN CELL TYPES. WE AND OTHERS HAVE USED HIGHLY SULFATED HS-LIKE GLYCOPOLYMERS TO TEST THE CRUCIAL ROLE OF HS IN THE INTERACTION AND IN VITRO REPLICATION OF PRIONS. HOWEVER, THE COMPOSITION OF ENDOGENOUS HS AND THEIR SPECIFIC ROLES IN HEALTHY AGED AND DISEASE-AFFECTED BRAIN ARE UNKNOWN. I FOUND THAT MICE EXPRESSING SHORTER HS CHAINS SHOWED PROLONGED SURVIVAL AND PROFOUNDLY ALTERED PRION PLAQUE DISTRIBUTION IN BRAIN WHEN INFECTED WITH A PLAQUE-FORMING PRION STRAIN, BUT DID NOT SHOW ANY CHANGE IN THE PRION DISEASE PHENOTYPE CAUSED BY AGGREGATE-FORMING PRIONS. HERE I WILL DEFINE THE HS MOLECULES THAT BIND TO PHYSIOLOGICAL AND MISFOLDED PRION PROTEIN IN DIFFERENT NEURONAL POPULATIONS. I HYPOTHESIZE THAT THE INTERACTION OF HS WITH MISFOLDED PRIONS IS A MAJOR DETERMINANT UNDERLYING THE SELECTIVE CELL VULNERABILITY IN PRION DISEASE. IN AIM 1, I WILL DETERMINE THE ROLE OF HS SULFATION IN THE PRION REPLICATION I) IN VITRO, USING HS ISOLATED FROM DISTINCT NEURONAL POPULATIONS, AND II) IN VIVO, BY MOUSE MODELS DEFICIENT IN HS SULFATION. I WILL MEASURE HOW THE VARIATION IN THE HS SULFATION IMPACTS THE PRP CELL TROPISM AND LESION TARGETS IN THE BRAIN, AND HOW AGE AFFECTS HS COMPOSITION. I WILL NEXT MANIPULATE THE HS COMPOSITION IN DIFFERENT NEURONAL POPULATIONS I) TO MEASURE THE SELECTIVE CELL UPTAKE OF PRIONS STR