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Rush University Medical Center, Brigham and Women’s Hospital, Harvard University, and the Broad Institute, Share $7.9 million NIH Grant to Explore Molecular Basis of Alzheimer’s Disease and Discover Novel Therapies

The National Institutes of Health announced on Wednesday the award of a new research grant to discover, characterize and validate complex molecular networks and candidate genes that influence susceptibility to cognitive decline and Alzheimer’s disease. The grant includes an effort to accelerate the translation of these discoveries into novel treatments.

Dr. Philip De Jager, of the Brigham and Women’s Hospital in Boston, and Harvard University, and the Broad Institute in Cambridge, and Dr. David Bennett of Rush University Medical School, Chicago, are the principal investigators for the study. The first year of funding is $1.7 million, with an expected total funding of $7.9 million. The Broad Institute and Rush are the lead organizations with involvement by Brigham and Women’s Hospital and the Pacific Northwest National Laboratories in Richland, Washington.

This award was among several new research grants totaling $45 million NIH announced on Wednesday to advance the National Plan to Address Alzheimer’s Disease, a national effort that aims to find effective interventions for Alzheimer’s by 2025.

“I am gratified that these awards are advancing the research directions that were identified at the NIH-hosted Alzheimer’s Summit of 2012,” said Dr. Neil Buckholtz, Director of the Division of Neuroscience at the National Institute on Aging, which leads the NIH Alzheimer’s research program. “The work being done by Drs. DeJager and Bennett and other researchers focused on identifying, characterizing and validating novel therapeutic targets may one day lead to promising targets for interventions for this dread disease.”

Using cutting-edge computational methods, the multi-disciplinary research team will analyze rich clinical, pathological, genomic and other large-scale molecular data collected from over 1,000 volunteers from the Religious Order Study and the Rush Memory and Aging Project, both based at Rush. Through “systems biology” approach, they will first identify cellular functions that are disrupted by Alzheimer’s disease and then screen for chemical compounds that correct these abnormal cellular functions. These investigations will therefore set the stage for the discovery of several known or novel compounds that could be used to treat Alzheimer’s disease.

“Our proposal brings together an exceptionally strong and unique multi-disciplinary team with the relevant skills needed to identify novel treatments for Alzheimer’s disease,” said De Jager.

The systems biology approach will be used to mine a unique set of clinical, neuropathologic, genomic, epigenomic, and transcriptomic data from the frozen brain tissue of 1,000 subjects from two cohort studies of aging and dementia conducted at Rush, the Religious Orders Study and the Rush Memory and Aging Project, according to Bennett.

“The unique data from these specimens provide an excellent substrate for the identification and and nomination of molecular targets for drug discovery,” said De Jager.

A flexible translational strategy that first validates targets by a proteomics study of brain tissue will follow, along with functional validation studies in cultured human neurons and astrocytes.

Then all of the data will come together when researchers perform high throughput small molecule screens on neurons and astrocytes derived from induced pluripotent stem cells (iPSC) on the most promising targets.

“This study is ambitious but realistic: it reflects the deployment of cutting-edge approaches with a practical mindset in which redundancies have been carefully considered to mitigate risk and ensure the delivery of data, network models and lead compounds,” said Bennett.

“We anticipate that we will discover and validate novel targets associated with molecular processes that lead to cognitive decline, and demonstrate the potential for drugs to impact one or more targets, setting the stage for clinical trials with new and novel approaches to the prevention and treatment of Alzheimer’s disease,” said De Jager.

The Religious Orders Study, the Rush Memory and Aging Project, and the multiple levels of other data were funded by grants from the National Institutes of Health. De Jager, Bennett, and the other investigators are grateful to the funding agency (Grant # U01AG46152) and the thousands of older persons from across the country participating in these studies.

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