DECIPHERING THE ROLE OF NORADRENERGIC RECEPTORS DURING NEUROMODULATION IN ALZHEIMER'S DISEASE - PROJECTIVE…
Federal financial assistance recorded from USAspending. This is not a procurement contract.
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ASST_NON_K00AG084261_075 · THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NE… · Department of Health and Human Services
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- Assistance award identifier
- ASST_NON_K00AG084261_075
- FAIN
- K00AG084261
- Recipient
- THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK
- Awarding agency
- Department of Health and Human Services
- Funding agency
- Department of Health and Human Services
- Assistance listing (CFDA)
- 93.866
- Total obligated
- $176,587
- Period
- Jul 1, 2021 – Mar 31, 2027
- Fiscal year
- 2023
- Place of performance state
- NY
- Source file
- FY2023_All_Assistance_Full_20261006.zip
Description
DECIPHERING THE ROLE OF NORADRENERGIC RECEPTORS DURING NEUROMODULATION IN ALZHEIMER'S DISEASE - PROJECTIVE SUMMARY ALZHEIMERâS DISEASE (AD), CHARACTERIZED BY ABNORMAL ACCUMULATION OF AMYLOID PLAQUES AND NEUROFIBRILLARY TANGLES WITHIN THE BRAIN, IS THE MOST COMMON FORM OF DEMENTIA FOR ADULTS AGED 65 AND UP AND THE 7TH LEADING CAUSE OF DEATH WORLDWIDE. DESPITE INITIAL DIAGNOSES OF AD OCCURRING OVER A CENTURY AGO, EFFECTIVE CLINICAL THERAPIES TO PREVENT OR TREAT DISEASE PROGRESSION ARE CURRENTLY LACKING. THE LOCUS COERULEUS (LC), AN IMPORTANT BRAINSTEM NUCLEI WHICH ACTS AS THE PRIMARY SOURCE OF NOREPINEPHRINE (NE) THROUGHOUT THE BRAIN, HAS BEEN IDENTIFIED AS ONE OF THE EARLIEST STRUCTURES TO DETERIORATE IN AD. LC DEGENERATION IS STRONGLY CORRELATED WITH SEVERITY OF COGNITIVE DECLINE, SUGGESTING STRATEGIES TO PRESERVE OR ENHANCE LC FUNCTION OFFER SIGNIFICANT THERAPEUTIC POTENTIAL. FURTHERMORE, NE POTENTIATES ESTABLISHED ANTI-INFLAMMATORY PROPERTIES AND IS KNOWN TO INDUCE MICROGLIA PHAGOCYTOSIS AND CLEARANCE OF AMYLOID IN AD. THEREFORE, PROMOTING NE RELEASE VIA LC STIMULATION IS AN EMERGING STRATEGY TO ALLEVIATE NEUROPATHOLOGY AND COGNITIVE DEFICITS IN AD. HOWEVER, THE MOLECULAR AND CELLULAR PROCESSES WHICH GOVERN THE POTENTIAL THERAPEUTIC EFFECTS OF THE LC-NE SYSTEM DURING AD PROGRESSION REMAIN UNKNOWN. THIS K00 RESEARCH STRATEGY PROPOSES A MULTI-MODAL APPROACH INVOLVING GENE EDITING, INTRAVITAL IMAGING, ELECTROPHYSIOLOGY, BEHAVIORAL TRAINING, AND SINGLE CELL SEQUENCING TO REVEAL THE FUNCTIONAL ROLE OF CELL-TYPE AND SUB-TYPE SPECIFIC NORADRENERGIC RECEPTORS DURING LC STIMULATION IN AD. IN AIM 1, A BASELINE WILL BE ESTABLISHED DETERMINING THE EXTENT IN WHICH LONG-TERM LC STIMULATION REDUCES NEUROINFLAMMATION, AMYLOID/TAU BURDEN, AND COGNITIVE IMPAIRMENT IN TWO DIFFERENT RODENT MODELS OF AD. IN AIM 2 AND 3, GENE EDITING WILL BE USED TO INTERFERE WITH SUB-TYPE SPECIFIC NORADRENERGIC RECEPTORS IN ASTROCYTES AND MICROGLIA, RESPECTIVELY, TO UNDERSTAND BOTH CELL-TYPE AND SUB