Big data and small molecules for alzheimer's disease

Active Project Grant Awarded Last action

Award ID
R01AG063913
Recipient
Awarding agency
Obligated
$4,088,872

Award facts

Assistance listing
93.866 Aging Research
Completion date 71% complete
Place of performance
Roxbury, MA 02118, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Alzheimer's disease (ad) is characterized by progressive loss of synapses and neurons along with amyloid and TAU pathologies. Although amyloid-β (AΒ)-reducing immunotherapy received full approval by the FDA for patients with mild cognitive impairment (MCI) or mild ad, developing future treatments against ad at all stages is an urgent priority. One of our recent 12 publications described our cohorts of patients with MCI, mild, moderate, or severe ad within the department of veterans affairs (VA) healthcare system. Using electronic health records (ehrs), we reported a slower progression to ad among veterans on prescribed vasodilators, including anti-hypertensive angiotensin converting enzyme inhibitors (aceis) and angiotensin receptor blockers (arbs). We compared a spectrum of anti-hypertension, anti-diabetic or anti-hypercholesterolemia medications and reported a reduced risk of ad onset among vasodilator users (e.g., valsartan, carvedilol, losartan) and an increased risk of ad onset among vasoconstrictor users (e.g., propranolol). We also reported that aceis reduced phosphorylated TAU (ptau) in mouse brains. We further reported that fasudil, a specific vasodilator and a RHO- associated coiled-coil kinase (rock) 1/2 inhibitor, decreased ptau in human neuro-spheroids. We therefore propose to perform data mining of 25 million veterans' 76 billion medical records from the VA corporate data warehouse and to test the clinical effectiveness of more potent vasodilators, such as a selective ROCK2 inhibitor belumosudil, in delaying ad onset among veterans. We will also test if belumosudil suppresses neurodegeneration in ad mouse models. Our access to VA EHR as well as our expertise in development and multidisciplinary analysis of familial ad mouse models place US in a unique position to test the hypothesis that vasodilation alleviates cognitive impairment in ad patients as well as memory deficits and neurodegeneration in ad mouse models. In this competing continuation application, we propose to evaluate the effects of more potent vasodilators on cognitive impairment of ad patients and ad mouse models (aim 1). We will perform big data analysis of EHR to collect vasodilators that are associated with delayed onset of ad, compared to the benchmark ARB drug valsartan. We will also test whether vasodilators, such as belumosudil, alleviate neurodegeneration and memory impairment in ad mouse models. We will also explore molecular mechanisms of vasodilators using single nucleus rnaseq and proteomic analyses of ad postmortem brains and mouse models (aim 2). The significant impact of the current study is that these small molecules derived from big data mining and validated in ad mouse models may be fast-tracked to next generation safe therapies of ad.

Transactions

Action Obligated Date
Amendment $2,417,411
Amendment $0
Amendment $801,219
Original award $870,242

Subawards

Subrecipient Amount Awarded
The Bedford VA Research Corporation. Inc. Ying Wang, Ph.D. will lead the programmer and statistician to extract big data set of medical records and perform statistical analysis for outcome… $41,322
Bentley University In this project, we will extend our current study on Alzheimer’s Disease progression after the early symptom, such as Mild cognitive impairment, cognitive… $54,022
Brigham & Womens Hospital Inc. Dr. Jie Shen has over 25 years of experience using genetics coupled with multidisciplinary approaches to investigate the pathogenetic mechanisms of… $843,672
The Methodist Hospital Research Institute Dr. Wong’s group will assist the PI and MPI to perform bioinformatics analysis of multi-omics data generated from animal tissue, blood and postmortem brain… $159,440

Quick answers

Who received award R01AG063913?

R01AG063913 was awarded to Trustees Of Boston University by National Institute on Aging (National Institutes of Health) on August 15, 2019.

How much is award R01AG063913 worth?

$4,088,872 has been obligated on R01AG063913.

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