Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA166009-02
Application #
8738618
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Spalholz, Barbara A
Project Start
2013-09-20
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost

  Institution

Name
University of Massachusetts Amherst
Department
Veterinary Sciences
Type
Earth Sciences/Resources
DUNS #
City
Amherst
State
MA
Country
United States
Zip Code
01003

  Publications

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
Ozay, E Ilker; Gonzalez-Perez, Gabriela; Torres, Joe A et al. (2016) Intracellular Delivery of Anti-pPKC? (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

Showing the most recent 10 out of 37 publications