This Program proposes an overarching hypothesis that rational targeting of ?-secretase, a multi-subunit intramembrane cleaving protease that has several biologically important substrates, may be considered as a therapeutic target for a number of diseases. The three projects in this Program address the use of ?-secretase inhibitors in breast cancer (Project 1), and graft-versus-host disease (Project 2), and propose biochemical strategies to enable us to better understand the mechanism of action of ?-secretase (Project 3). These projects are integrated with a goal of better understanding the mechanism of action of ?-secretase inhibition in normal, as well as, disease settings. The Principal Investigators of this Program have worked together, shared data and published as a group for the past six years. The Program is significantly enhanced by a Chemistry Core that has the proven ability to synthesize a wide variety of ?-secretase inhibitors that allow members of the Program to explore the biological properties of these inhibitors in an environment free from commercial restriction. Such an approach will provide a scientific basis for optimal GSI selection matched to a particular disease.

Public Health Relevance

The development of y-secretase inhibitors targeted for therapy of diseases such as cancer and graft-versus host- disease is likely to significantly impact the treatment of these two important diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA166009-01A1
Application #
8415150
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (O1))
Program Officer
Spalholz, Barbara A
Project Start
2013-09-20
Project End
2017-08-31
Budget Start
2013-09-20
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$980,825
Indirect Cost
$163,430
Name
University of Massachusetts Amherst
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
153926712
City
Amherst
State
MA
Country
United States
Zip Code
01003
Hossain, Fokhrul; Sorrentino, Claudia; Ucar, Deniz A et al. (2018) Notch Signaling Regulates Mitochondrial Metabolism and NF-?B Activity in Triple-Negative Breast Cancer Cells via IKK?-Dependent Non-canonical Pathways. Front Oncol 8:575
Chandiran, Karthik; Lawlor, Rebecca; Pannuti, Antonio et al. (2018) Notch1 primes CD4 T cells for T helper type I differentiation through its early effects on miR-29. Mol Immunol 99:191-198
Hossain, Fokhrul; Majumder, Samarpan; Ucar, Deniz A et al. (2018) Notch Signaling in Myeloid Cells as a Regulator of Tumor Immune Responses. Front Immunol 9:1288
Dawson, Ted M; Golde, Todd E; Lagier-Tourenne, Clotilde (2018) Animal models of neurodegenerative diseases. Nat Neurosci 21:1370-1379
Ran, Yong; Hossain, Fokhrul; Pannuti, Antonio et al. (2017) ?-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct. EMBO Mol Med 9:950-966
Sgolastra, Federica; Backlund, Coralie M; Ilker Ozay, E et al. (2017) Sequence segregation improves non-covalent protein delivery. J Control Release 254:131-136
Sarapas, Joel M; Backlund, Coralie M; deRonde, Brittany M et al. (2017) ROMP- and RAFT-Based Guanidinium-Containing Polymers as Scaffolds for Protein Mimic Synthesis. Chemistry 23:6858-6863
Aquila, Giorgio; Fortini, Cinzia; Pannuti, Antonio et al. (2017) Distinct gene expression profiles associated with Notch ligands Delta-like 4 and Jagged1 in plaque material from peripheral artery disease patients: a pilot study. J Transl Med 15:98
Moyano, Daniel F; Liu, Yuanchang; Ayaz, Furkan et al. (2016) Immunomodulatory effects of coated gold nanoparticles in LPS-stimulated in vitro and in vivo murine model systems. Chem 1:320-327
Pannella, Micaela; Caliceti, Cristiana; Fortini, Francesca et al. (2016) Serum From Advanced Heart Failure Patients Promotes Angiogenic Sprouting and Affects the Notch Pathway in Human Endothelial Cells. J Cell Physiol 231:2700-10

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