Gamma-secretase is a fascinating multi-subunit intramembrane cleaving protease that is now being considered as a therapeutic target for a number of diseases. Primarily because gamma-secretase was a therapeutic target in Alzheimer's disease (AD), a number of GSIs have been developed that effectively inhibit gamma-secretase cleavage in humans. In humans with AD, long-term treatment with current GSIs appears to have mechanism based side-effects that limit the maximum tolerable dose to the point where the extent of long-term AB lowering is likely to be insufficient to have clinical impact in symptomatic patients. However, as elaborated on in Projects 1 and 2, because of its role in mediating signaling events from other proteins, with a primary focus on Notch signaling;gamma-secretase is a therapeutic target in cancer and immunologic disease and may very well be a target in other diseases, as long as the treatment window is acute, subacute or intermittent. Given the preliminary and published data in Projects 1 and 2 of this proposal as well as data from others supporting the repurposing of GSIs for multiple disease indications, further exploration of this ongoing repurposing effort is warranted. A major challenge when considering repurposing of GSIs is that the study of gamma-secretase cleavage has been dominated by its focus on APP and Notch 1. GSIs in AD are thought of as AB inhibitors and in cancer as Notch 1 inhibitors, but what about the GSI action on the nearly 100 additional substrates identified to date? Are these cleavages relevant or irrelevant to the biology of the system being investigated? Indeed, the major working hypothesis of this project is that in order to understand the biological role of gamma-secretase and appropriately repurpose GSIs for a given disease indication a fuller appreciation of gamma-secretase activity and the substrate inhibitory profiles of GSIs are needed. The studies proposed will enable facile assessment of cleavage of a broader repertoire of gamma-secretase substrates;guide the repurposing efforts for GSIs as therapeutics in cancer, GVHD and other emerging indications, and enable us to determine whether gamma-secretase cleavage is altered in aging or AD.

Public Health Relevance

This research is relevant to public health as it will help insure that drugs (gamma-secretase inhibitors, GSIs) developed for use in Alzheimer's disease are optimally repurposed as therapeutics for cancer and immunologic diseases. Our research aligns with the NIH's mission by guiding further therapeutic development of drugs already tested in humans and thereby has the potential to reduce disease burden.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Amherst
United States
Zip Code
Ozay, E Ilker; Gonzalez-Perez, Gabriela; Torres, Joe A et al. (2016) Intracellular Delivery of Anti-pPKCθ (Thr538) via Protein Transduction Domain Mimics for Immunomodulation. Mol Ther 24:2118-2130
deRonde, Brittany M; Posey, Nicholas D; Otter, Ronja et al. (2016) Optimal Hydrophobicity in Ring-Opening Metathesis Polymerization-Based Protein Mimics Required for siRNA Internalization. Biomacromolecules 17:1969-77
Gordon, Mallory R; Canakci, Mine; Li, Longyu et al. (2015) Field Guide to Challenges and Opportunities in Antibody-Drug Conjugates for Chemists. Bioconjug Chem 26:2198-215
Yun, Jieun; Espinoza, Ingrid; Pannuti, Antonio et al. (2015) p53 Modulates Notch Signaling in MCF-7 Breast Cancer Cells by Associating With the Notch Transcriptional Complex Via MAML1. J Cell Physiol 230:3115-27
Kuksin, Christina Arieta; Minter, Lisa M (2015) The Link between Autoimmunity and Lymphoma: Does NOTCH Signaling Play a Contributing Role? Front Oncol 5:51
Park, Hyo-Jin; Ran, Yong; Jung, Joo In et al. (2015) The stress response neuropeptide CRF increases amyloid-β production by regulating γ-secretase activity. EMBO J 34:1674-86
Wongchana, Wipawee; Lawlor, Rebecca G; Osborne, Barbara A et al. (2015) Impact of Notch1 Deletion in Macrophages on Proinflammatory Cytokine Production and the Outcome of Experimental Autoimmune Encephalomyelitis. J Immunol 195:5337-46
deRonde, Brittany M; Torres, Joe A; Minter, Lisa M et al. (2015) Development of Guanidinium-Rich Protein Mimics for Efficient siRNA Delivery into Human T Cells. Biomacromolecules 16:3172-9
Jung, Joo In; Price, Ashleigh R; Ladd, Thomas B et al. (2015) Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator. Mol Neurodegener 10:29
Arieta Kuksin, Christina; Gonzalez-Perez, Gabriela; Minter, Lisa M (2015) CXCR4 expression on pathogenic T cells facilitates their bone marrow infiltration in a mouse model of aplastic anemia. Blood 125:2087-94

Showing the most recent 10 out of 24 publications