We seek to understand the molecular mechanism underlying the tissue degeneration characteristic of human amyloid diseases and to use this insight to develop new therapeutic strategies and diagnostics to ameliorate the human amyloidoses.
In specific aim 1, we focus on understanding why aging is such an important risk factor for the onset of the transthyretin amyloidoses. All indications are that amyloid diseases do not result from slow, progressive accumulation of amyloid fibrils over a lifespan. Instead, an aging-related physiological change appears to trigger their onset. Since transthyretin is synthesized and degraded by the liver, and since liver transplantation from an amyloid patient into a liver cancer patient initiates rapid amyloidosis in the latter, we are confident that studying liver physiology in amyloidosis, and normal young and old donors will reveal important clues about the etiology of this disease.
In specific aim 2, we utilize first-in-class amyloidogenesis inhibitors to test the amyloid hypothesis in two placebo-controlled human clinical trials. We will also fractionate specific aggregate morphologies, arrest these intermediates from further assembly and assess their toxicity. Additionally, new technology will be developed to characterize amyloid deposits in the context of the oxidative-metabolite pool, which could contribute to these maladies.
In specific aim 3, we will continue to develop new therapeutic strategies centered around the discovery of secretion modulators, compounds that make cells less permissive to the secretion of highly destabilized amyloidogenic proteins. Unlike the transthyretin-disease specific native state kinetic stabilizers discovered in the last funding period, these compounds should be useful in treating numerous amyloid diseases. Lastly, we seek to develop positron emission tomography (PET) diagnostics to image the earliest aggregates appearing in amyloid diseases in living subjects to enable treatment to begin before substantial tissue degeneration occurs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK046335-22
Application #
8507718
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Bishop, Terry Rogers
Project Start
1993-05-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
22
Fiscal Year
2013
Total Cost
$561,126
Indirect Cost
$264,969
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Rappley, Irit; Monteiro, CecĂ­lia; Novais, Marta et al. (2014) Quantification of transthyretin kinetic stability in human plasma using subunit exchange. Biochemistry 53:1993-2006
Zhang, Xin; Liu, Yu; Genereux, Joseph C et al. (2014) Heat-shock response transcriptional program enables high-yield and high-quality recombinant protein production in Escherichia coli. ACS Chem Biol 9:1945-9
Baranczak, Aleksandra; Connelly, Stephen; Liu, Yu et al. (2014) Fluorogenic small molecules requiring reaction with a specific protein to create a fluorescent conjugate for biological imaging-what we know and what we need to learn. Biopolymers 101:484-95
Liu, Yu; Zhang, Xin; Tan, Yun Lei et al. (2014) De novo-designed enzymes as small-molecule-regulated fluorescence imaging tags and fluorescent reporters. J Am Chem Soc 136:13102-5
Penchala, Sravan C; Connelly, Stephen; Wang, Yu et al. (2013) AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin. Proc Natl Acad Sci U S A 110:9992-7
Shoulders, Matthew D; Ryno, Lisa M; Genereux, Joseph C et al. (2013) Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell Rep 3:1279-92
Suh, Eul Hyun; Liu, Yu; Connelly, Stephen et al. (2013) Stilbene vinyl sulfonamides as fluorogenic sensors of and traceless covalent kinetic stabilizers of transthyretin that prevent amyloidogenesis. J Am Chem Soc 135:17869-80