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Biochem Pharmacol. 2014 Apr 15;88(4):617-30. doi: 10.1016/j.bcp.2014.01.037. Epub 2014 Feb 6.

Building a pipeline to discover and validate novel therapeutic targets and lead compounds for Alzheimer's disease.

Author information

1
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, United States. Electronic address: David_A_Bennett@Rush.edu.
2
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, United States. Electronic address: Lei_Yu@Rush.edu.
3
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States. Electronic address: pdejager@partners.org.

Abstract

Cognitive decline, Alzheimer's disease (AD) and other causes are major public health problems worldwide. With changing demographics, the number of persons with dementia will increase rapidly. The treatment and prevention of AD and other dementias, therefore, is an urgent unmet need. There have been considerable advances in understanding the biology of many age-related disorders that cause dementia. Gains in understanding AD have led to the development of ante-mortem biomarkers of traditional neuropathology and the conduct of several phase III interventions in the amyloid-β cascade early in the disease process. Many other intervention strategies are in various stages of development. However, efforts to date have met with limited success. A recent National Institute on Aging Research Summit led to a number of requests for applications. One was to establish multi-disciplinary teams of investigators who use systems biology approaches and stem cell technology to identify a new generation of AD targets. We were recently awarded one of three such grants to build a pipeline that integrates epidemiology, systems biology, and stem cell technology to discover and validate novel therapeutic targets and lead compounds for AD treatment and prevention. Here we describe the two cohorts that provide the data and biospecimens being exploited for our pipeline and describe the available unique datasets. Second, we present evidence in support of a chronic disease model of AD that informs our choice of phenotypes as the target outcome. Third, we provide an overview of our approach. Finally, we present the details of our planned drug discovery pipeline.

KEYWORDS:

Alzheimer's disease; RNAi; Small molecule screen; Systems biology; Targeted proteomics

PMID:
24508835
PMCID:
PMC4054869
DOI:
10.1016/j.bcp.2014.01.037
[Indexed for MEDLINE]
Free PMC Article

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