My research focuses on understanding the amyloidogenic nature of transthyretin (TTR), normally a soluble protein present in plasma and cerebral spinal fluid. Both wild-type and specific variant forms of TTR can be amyloidogenic, but disease onset is delayed in what appears to be an age-dependent mechanism. Our investigations are aimed at identifying specific age-related factors required to initiate the disease process; these factors likely include structural features that are both intrinsic and extrinsic to TTR. My research attempts to link protein biochemistry to disease pathology by studying the role of amino acid alterations, post-translational modifications (glycosylation, sulfonation, cysteinylation and phosphorylation) and metabolic processing in TTR amyloid fibril formation. We have precisely defined the molecular composition of numerous amyloidogenic TTR proteins derived from patient serum and tissue samples using mass spectrometry, analytical ultracentrifugation, and electron microscopy. In addition, using a proteomic approach, we have identified several tissue components present in patient specimens which may be effectors of amyloidogenesis. With recombinantly-generated proteins, we are studying the molecular stability of various forms of TTR, as well as the heteroassociations of TTR with these deposited molecular constituents using electrophoretic, chromatographic, and histological techniques. A translational component of our studies involves the study of a variety of compounds, including the small molecules diflunisal and a-tocopherol, as potential inhibitors of TTR aggregation and fibril formation. Furthermore, since TTR-associated amyloid diseases often feature cardiomyopathies, we are also studying the direct and indirect effects of amyloidogenic forms of TTR on cultured primary cardiac cells.
- Graduate Faculty (Primary Mentor of Grad Students), Boston University School of Medicine, Division of Graduate Medical Sciences
- Associate Professor, Biochemistry, Boston University School of Medicine
- Boston University, PhD
- Tufts University, MS
- Boston College, BS
- Published on 7/21/2018
Giadone RM, Rosarda JD, Akepati PR, Thomas AC, Boldbaatar B, James MF, Wilson AA, Sanchorawala V, Connors LH, Berk JL, Wiseman RL, Murphy GJ. A library of ATTR amyloidosis patient-specific induced pluripotent stem cells for disease modelling and in vitro testing of novel therapeutics. Amyloid. 2018 Jul 21; 1-8. PMID: 30032658.
- Published on 6/25/2018
Klimtchuk ES, Prokaeva T, Frame NM, Abdullahi HA, Spencer B, Dasari S, Cui H, Berk JL, Kurtin PJ, Connors LH, Gursky O. Unusual duplication mutation in a surface loop of human transthyretin leads to an aggressive drug-resistant amyloid disease. Proc Natl Acad Sci U S A. 2018 Jul 10; 115(28):E6428-E6436. PMID: 29941560.
- Published on 6/19/2018
Mints YY, Doros G, Berk JL, Connors LH, Ruberg FL. Features of atrial fibrillation in wild-type transthyretin cardiac amyloidosis: a systematic review and clinical experience. ESC Heart Fail. 2018 Jun 19. PMID: 29916559.
- Published on 2/9/2018
Phull P, Sanchorawala V, Connors LH, Doros G, Ruberg FL, Berk JL, Sarosiek S. Monoclonal gammopathy of undetermined significance in systemic transthyretin amyloidosis (ATTR). Amyloid. 2018 Mar; 25(1):62-67. PMID: 29424556.
- Published on 2/1/2018
Hanson JLS, Arvanitis M, Koch CM, Berk JL, Ruberg FL, Prokaeva T, Connors LH. Use of Serum Transthyretin as a Prognostic Indicator and Predictor of Outcome in Cardiac Amyloid Disease Associated With Wild-Type Transthyretin. Circ Heart Fail. 2018 Feb; 11(2):e004000. PMID: 29449366.
- Published on 10/20/2017
Arvanitis M, Chan GG, Jacobson DR, Berk JL, Connors LH, Ruberg FL. Prevalence of mutant ATTR cardiac amyloidosis in elderly African Americans with heart failure. Amyloid. 2017 Dec; 24(4):253-255. PMID: 29052438.
- Published on 9/27/2017
Chan GG, Koch CM, Connors LH. Serum Proteomic Variability Associated with Clinical Phenotype in Familial Transthyretin Amyloidosis (ATTRm). J Proteome Res. 2017 Nov 03; 16(11):4104-4112. PMID: 28922609.
- Published on 7/29/2017
Prokaeva T, Akar H, Spencer B, Havasi A, Cui H, O'Hara CJ, Gursky O, Leszyk J, Steffen M, Browning S, Rosenberg A, Connors LH. Hereditary Renal Amyloidosis Associated With a Novel Apolipoprotein A-II Variant. Kidney Int Rep. 2017 Nov; 2(6):1223-1232. PMID: 29270531.
- Published on 6/20/2017
Klimtchuk ES, Prokaeva TB, Spencer BH, Gursky O, Connors LH. In vitro co-expression of human amyloidogenic immunoglobulin light and heavy chain proteins: a relevant cell-based model of AL amyloidosis. Amyloid. 2017 Jun; 24(2):115-122. PMID: 28632419.
- Published on 3/1/2017
Benson MD, Berk JL, Connors LH, Dasgupta NR. Familial wild-type transthyretin cardiomyopathy. Amyloid. 2017 Mar; 24(sup1):91-92. PMID: 28434303.
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