Lawreen H. Connors, Ph.D.

Associate Professor of Pathology and Biochemistry

Director, Gerry Amyloid Research Laboratory,
The Amyloidosis Center 
Co-director, Amyloid Pathology and Molecular Testing Laboratory, Boston Medical Centerlhc

Affiliations:

  • Department of Pathology and Laboratory Medicine, Boston University School of Medicine (BUSM)
  • Biochemistry, BUSM

Education:

  • Boston College, B.S. (Chemistry, Mathematics)
  • Tufts University, M.S. (Chemistry)
  • Boston University, Ph.D. (Biochemistry)

Board Membership: Amyloid Journal Editorial Board member

Professional Societies: International Society for Amyloidosis

Research Interests:

  • Principal Investigator:  Molecular mechanism of senile cardiac amyloidosis (NIH / R01-AG031804)
  • Principal Investigator:  Blood Profiling for Biomarkers in Age-related ‘Senile’ Systemic Amyloidosis, SSA (E. Rhodes and Leona B. Carpenter Foundation Grant)
  •  Co-Investigator: Novel insights of pathogenesis of light chain cardiac amyloidosis (NIH / R21-HL095891-01A1)
  • Co-Investigator: Studies of murine antibody 2A4 and AL LC amyloid tissues/purified proteins (Neotope Biosciences Sponsored Research Grant)
  • Consultant: Oxidative stress, matrix remodeling, and stem cell transplant in cardiac amyloidosis (AHA NCRP, NSDG)

The systemic amyloid diseases are protein misfolding and deposition disorders.  These pathologies feature the destabilization of one of several plasma proteins; the amyloidogenic protein adopts a non-native conformation that leads to aberrant self-association and aggregation.  The aggregates form defined fibrillar structures which ultimately precipitate as amyloid deposits in the extracellular compartments of targeted tissues/organs.  In addition to the mechanical disruption of tissue function by the deposited amyloid fibrils, pathological effects are thought to be related to the acute cellular toxicity of soluble prefibrillar amyloid aggregates. 

We are studying the amyloidogenic nature of transthyretin (TTR), normally a soluble protein present in plasma and cerebral spinal fluid.  Both wild-type and variant forms of TTR can form amyloid deposits, but disease onset is delayed in what appears to be an age-dependent mechanism.  Our investigations are aimed at identifying specific factors required to initiate the disease process; these factors likely include structural features that are both intrinsic and extrinsic to TTR.  Specific areas of interest include the roles of amino acid alterations, post-translational modifications (glycosylation, sulfonation, cysteinylation) and heteroassociations in TTR amyloid fibril formation. 

We have extensively characterized TTR proteins derived from clinical specimens and identified proteomic differences in patient vs. age-matched control serum and tissue samples.  TTR structural modifications and heteroassociations identified in the clinical samples are studied in vitro with recombinantly-generated proteins and several compounds, including diflunisal and α-tocopherol, are being investigated as potential inhibitors of TTR aggregation and fibril formation.  Furthermore, since TTR-associated amyloid diseases often feature cardiomyopathy, we are also studying the effects of amyloidogenic forms of TTR on cultured primary cardiac cells.

Selected Publications:

  • Phay M, Blinder V, Macy S, Greene MJ, Wooliver DC, Liu W, Planas A, Walsh DM, Connors LH, Primmer SR, Planque SA, Paul S, and O’Nuallain B:  Transthyretin aggregate-specific antibodies recognize cryptic epitopes on patient-derived amyloid fibrils.  Rejuvenation Res, 17(2):97-104, 2014.
  • Reddi HV, Jenkins S, Theis J, Thomas BC, Connors LH, Van Rhee F, and Highsmith WE Jr:  Homozygosity for the V122I mutation in transthyretin is associated with earlier onset of cardiac amyloidosis in the African American population in the seventh decade of life.  J Mol Diagnostics, 16(1):68-74, 2014.
  • Leung A, Nah SK, Reid W, Ebata A, Koch CM, Monti S, Genereux JC, Wiseman RL, Wolozin B, Connors LH, Berk JL, Seldin DC, Mostoslavsky G, Kotton DN, and Murphy GJ:  Induced pluripotent stem cell modeling of multisystemic, hereditary transthyretin amyloidosis.  Stem Cell Reports, 1(5):451-63, 2013.
  • Tanaka K, Essick EE, Doros G, Tanriverdi K, Connors LH, Seldin DC, and Sam F:  Circulating matrix metalloproteinases and tissue inhibitors of metalloproteinases in cardiac amyloidosis.  J Am Heart Assoc, Mar 12;2(2):e005868, 2013.
  • Guan J, Mishra S, Shi J, Plovie E, Qiu Y, Cao X, Gianni D, Jiang B, Del Monte F, Connors LH, Seldin DC, Lavatelli F, Rognoni P, Palladini G, Merlini G, Falk RH, Semigran MJ, Dec GW Jr, MacRae CA, and Liao R:  Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity.  Basic Res Cardiol, 108(5): 378, 2013.
  • Mishra S, Guan J, Plovie E, Seldin DC, Connors LH, Merlini G, MacRae CA, and Liao R:  Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death and early mortality in zebrafish.  Am J Physiol Heart Circ Physiol, 305(1):H95-H103, 2013.
  • Kingsbury JS, Laue TM, Chase SF, and Connors LH:  Detection of high molecular weight amyloid serum protein complexes using Biological On-Line Tracer Sedimentation (BOLTS).  Anal Biochem, Accepted for Publication, 2012.
  • Ramamurthy S, Connors LH, and O’Hara CJ:  Bone marrow biopsy and its utility in the diagnosis of AL Amyloidosis and other plasma cell dyscrasias (Chapter 23).  In:  Amyloid and Related Disorders: Surgical Pathology and Clinical Correlations, Springer Press, 2012, pp. 283-90.
  • Connors LH, Doros G, Sam F, Badiee A, Seldin DC, and Skinner M:  Clinical features and survival in senile systemic amyloidosis: comparison to familial transthyretin cardiomyopathy.  Amyloid:Journal of Protein Folding Disorders, 18 (Suppl 1):157-9, 2011.
  • Greene MJ, Sam F, Soohoo P, Patel R, Seldin DC, and Connors LH:  Evidence for a functional role of the molecular chaperone clusterin in amyloidotic cardiomyopathy.  J Am Path, 178(1):61-8, 2011.
  • Hovey BM, Ward JE, Soo Hoo, O’Hara C, Connors LH, and Seldin DC:  Preclinical development of siRNA therapeutics for AL amyloidosis. Gene Therapy, 18(12):1150-6, 2011.
  • Seldin DC, Andrea N, Berenbaum I, Berk JL, Connors LH, Dember LM, Doros G, Fennessey S, Finn K, Girnius S, Lerner A, Libbey C, Meier-Ewert H, O’Connell R, Quillen K, Ruberg FL, Sam F, Segal A, Shelton A, Skinner M, Sloan JM, Wiesman JF, and Sanchorawala V:  High dose melphalan and autologous stem cell transplantation for AL amyloidosis: recent trends in treatment-related mortality and one-year survival at a single institution.  XIIth International Symposium on Amyloidosis, Amyloid: J Prot Folding Disorders, 2011.
  • Ward JE, SooHoo P, O’Hara C, Toraldo G, Jasuja R, Guan J, Liao R, Connors LH, and Seldin DC:  A transgenic mouse model of AL amyloidosis and its use in testing oral therapeutics.  Blood, 118(25):6610-7, 2011.
  • Ward JE, SooHoo P, Toraldo G, Jasuja R, Connors LH, O’Hara C, and Seldin DC:  Metabolic phenotype in an AL amyloidosis transgenic mouse model.  Amyloid:Journal of Protein Folding Disorders, 18 (Suppl 1):40-41, 2011.
  • Weng L, Spencer B, Soo Hoo P, Connors LH, O’Hara C, and Seldin DC:  Dysregulation of miRNAs in AL amyloidosis.  Amyloid:Journal of Protein Folding Disorders, 18(3):128-35, 2011.
  • Klimtchuk ES, Gursky O, Patel R, Laporte KL, Connors LH, Skinner M, Seldin DC: The critical role of the constant region in thermal stability and aggregation of amyloidogenic immunoglobulin light chain.  Biochemistry, 49: 9848-9857, 2010.
  • Ren R, Hong Z, Gong H, Laporte K, Skinner M, Seldin DC, Costello CE, Connors LH, and Trinkaus-Randall V: The role of glycosaminoglycan sulfation in the formation of immunoglobulin light chain amyloid oligomers and fibrils.  J Biol Chem, 285(48):37672-82, 2010.
  • Shi J, Guan J, Jiang B, Brenner D, del Monte F, Ward J, Connors LH, Sawyer D, Semigran M, Macgillivray T, Seldin D, Falk R, and Liao R: Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38a MAPK pathway.  Proc Natl Acad Sci USA 107(9):4188-93, 2010.