GENERATION OF NEW NEURONS IN THE AGING ADULT BRAIN: IDENTIFYING MECHANISMS OF ADULT NEUROGENESIS BY EXPLOIT…

Assistance award details

Assistance award identifier

ASST_NON_R00AG090813_075

FAIN

R00AG090813

Recipient

NEW YORK UNIVERSITY

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

Apr 1, 2025 – Apr 30, 2029

Fiscal year

2026

Place of performance state

NY

Source file

FY2026_All_Assistance_Full_20261006.zip

Description

GENERATION OF NEW NEURONS IN THE AGING ADULT BRAIN: IDENTIFYING MECHANISMS OF ADULT NEUROGENESIS BY EXPLOITING SINGLE CELL SPATIAL TRANSCRIPTOMICS. - PROJECT SUMMARY: DISCOVERY OF GLIA-TO-NEURON IDENTITY CONVERSION HAS OPENED THE DOOR FOR GENERATION OF NEW NEURONS TO REPLACE THOSE LOST TO INJURY, AGING OR NEURODEGENERATIVE DISEASE INCLUDING HUNTINGTON’S DISEASE (HD) AND FRONTOTEMPORAL DEMENTIA (FTD). TO THIS, I HAVE USED A THERAPEUTICALLY VIABLE APPROACH TO SUCCESSFULLY GENERATE NEW NEURONS IN THE NEUROGENIC NICHES OF THE AGED ADULT MOUSE BRAIN BY TRANSIENTLY SUPPRESSING THE RNA BINDING PROTEIN POLYPYRIMIDINE TRACT BINDING PROTEIN-1 (PTBP1) USING AN ANTISENSE OLIGONUCLEOTIDE (ASO) DELIVERED BY A SINGLE INJECTION INTO CEREBRAL SPINAL FLUID. I FURTHER IDENTIFIED THAT RADIAL GLIAL-LIKE AND SUBEPENDYMAL-LIKE CELLS (NOT ASTROCYTES) CONVERT INTO NEW NEURONS OVER A TWO-MONTH PERIOD, ACQUIRE MATURE NEURONAL CHARACTER, AND FUNCTIONALLY INTEGRATE INTO ENDOGENOUS CIRCUITS THAT MODIFY MOUSE BEHAVIOR. NOT YET ESTABLISHED ARE THE MOLECULAR EVENTS UNDERLYING GLIA-INTO-NEURON IDENTITY CONVERSION, INCLUDING IDENTIFICATION OF THE INITIATING GLIAL CELL(S), THE EVENTS DRIVING ITS CONVERSION AND SUBSEQUENT MATURATION INTO A FUNCTIONAL NEURON, AND APPLICATION TO HD AND FTD. ADDITIONALLY, THE CHALLENGES PERTAINING TO ASTROCYTE-INTO-NEURON CONVERSION UPON PTBP1 REDUCTION HAVE YET TO BE RESOLVED. IN THIS PROPOSAL, I WILL UTILIZE COMBINATION OF TRADITIONAL SINGLE NUCLEAR SEQUENCING AND IMMUNOFLUORESCENCE WITH A TRANSFORMATIVE SINGLE CELL SPATIAL TRANSCRIPTOMICS TECHNOLOGY, TERMED MULTIPLEXED ERROR ROBUST FLUORESCENCE IN SITU HYBRIDIZATION (MERFISH), TO DEFINE THE PATHWAY(S) OF GENERATION OF NEW NEURONS IN AGED NEUROGENIC NICHES FOLLOWING A THERAPEUTICALLY VIABLE INJECTION TO PRODUCE TRANSIENT, ASO-MEDIATED SUPPRESSION OF SYNTHESIS AND ACCUMULATION OF PTBP1. I WILL THEN EXTEND THE EFFORT TO TEST IN MOUSE MODELS OF FRONTOTEMPORAL DEMENTIA ( FTD) AND HUNTINGTON’S DISEASE (HD) WHETHER GLIA-T