We will provide the Alzheimer?s disease (AD) community with a novel assay resource based on advanced methodology that enables precise, highly specific, standardizable, multiplex quantification of the innate immunity- complement protein network in AD brain tissues. The innate immune response and its ties to inflammation are important to the pathophysiology of AD (see Pubmed IDs: 31654430, 30740661, 32046242, 31427930, 31702392, 31907273). For example, in AD, a neuroinflammatory response is associated with fibrillar plaques, and elevated levels of inflammatory proteins are detectable in AD brains. Innate immune response proteins (e.g. complement proteins) are associated with amyloid plaques in human AD brains, and the complement cascade can be directly activated in vitro by fibrillar Ab and neurofibrillary tangles. As stated in a recent review (PMID: 31907273), ?Quantitative studies on the balance between activators and inhibitors of complement in injured brain and the influence of the complotype on progression of AD could be useful in designing personalized therapies in the future. Although much remains to be clarified, targeting specific effector pathways of complement is justified now as a potential therapeutic strategy for this debilitating neurodegenerative disease.? Regulation of the immune system is the result of interplay amongst many 100s of proteins, and it will no doubt be important to quantify these regulatory networks in order to deliver new immunotherapies effectively (e.g., personalized medicine?) and to develop new immunotherapies (many of these proteins may themselves be viable therapeutic targets, or modulated in response to effective immune therapies). Furthermore, conventional protein quantification approaches (e.g. immunoassays) typically target one analyte at a time, which is not adequate for studying the behavior of a complex and robust signaling network such as innate immunity. We will develop multiplex assays to quantify proteins in the innate immune network, using a NextGen protein quantification platform based on a targeted form of mass spectrometry called multiple reaction monitoring (MRM). All assay protocols and validation data will be made publicly available as a novel resource to the community via the established, open-source NCI Assay Portal (assays.cancer.gov). We believe that this work is likely to stimulate additional work leading to progress on AD by providing the AD community with a novel assay resource based on advanced methodology that enables precise, highly specific, standardizable, multiplex quantification of the inflammation / innate immunity protein network in AD brains.

Public Health Relevance

The following is the project narrative from the parent application. See Research Strategy for details on the ad- ministrative supplement activities. Ovarian cancer, the most lethal gynecological malignancy, is diagnosed in more than 225,000 women worldwide each year. Despite improvements in surgical and chemotherapy approaches, overall survival has not changed significantly for decades, due to the presence of drug-resistant cancer cells that enable tumor progression. Our project brings together an interdisciplinary team of ovarian cancer doctors and translational research experts to use novel approaches to understand how drug resistance develops in ovarian cancer, and to discover new ther- apies to overcome resistance.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Rodriguez, Henry
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Fred Hutchinson Cancer Research Center
United States
Zip Code
Whiteaker, Jeffrey R; Zhao, Lei; Ivey, Richard G et al. (2018) Targeted mass spectrometry enables robust quantification of FANCD2 mono-ubiquitination in response to DNA damage. DNA Repair (Amst) 65:47-53
Collins, Christopher J; Chang, Irene J; Jung, Sunhee et al. (2018) Rapid Multiplexed Proteomic Screening for Primary Immunodeficiency Disorders From Dried Blood Spots. Front Immunol 9:2756
Salter, Alexander I; Ivey, Richard G; Kennedy, Jacob J et al. (2018) Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function. Sci Signal 11:
Whiteaker, Jeffrey R; Zhao, Lei; Saul, Rick et al. (2018) A Multiplexed Mass Spectrometry-Based Assay for Robust Quantification of Phosphosignaling in Response to DNA Damage. Radiat Res 189:505-518