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Iris Lindberg, PhD

Academic Title:

Professor

Primary Appointment:

Anatomy and Neurobiology

Secondary Appointment(s):

BioChemistry&Molecular Biology

Additional Title:

Professor

Location:

HSF-II S267

Phone (Primary):

410-706-4778

Education and Training

  • University of California at Berkeley, A.B. Biochemistry 1975
  • University of Wisconsin at Madison, Ph.D., 12/1980
  • Post-Doctorate, NIH (NIMH), Neuropharmacology, 1981-1984

Biosketch

All multicellular organisms use signaling molecules to convey information between cells. Neurons and endocrine tissues- the brain, pituitary, pancreas and adrenal gland- secrete especially important signaling molecules: peptidergic neurotransmitters, such as opioid peptides (the brain’s endogenous opiates); and peptide hormones, for example insulin. Dr. Lindberg’s major research questions center on the control of the production of bioactive peptides by specific synthesizing enzymes, the enzymes known as proprotein convertases. A second important focus is the role of anti-aggregant chaperone proteins in endocrine and neural tissues. As described further below, these two research areas relate specifically to two diseases: diabetes/ obesity and neurodegeneration.

Dr. Lindberg has made major contributions in the field of peptide hormone synthesis, most recently with regard to human PCSK1 mutations; her recent work on chaperone action in neurodegeneration has shown that the brain contains natural secretory chaperone proteins that may be exploited to combat neurodegenerative diseases, since many involve abnormal protein aggregation. Dr. Lindberg has been continuously funded by the National Institutes of Health since 1985, and has published over 141 peer-reviewed papers, invited reviews, and book chapters, with over 5700 citations.

Research/Clinical Keywords

Peptide hormones, obesity, proprotein convertases, diabetes, neurodegeneration, Alzheimer’s disease, Parkinson’s disease, protein chaperones

Highlighted Publications

Ramos-Molina, B., and Lindberg, I. (2015) Phosphorylation and alternative splicing of 7B2 reduce prohormone convertase 2 activation. Mol. Endocrinol. 29:756-64. PMID:25811241

Ramos-Molina, B., Lick, A. N., Blanco, E.H., Posada-Salgado, A., Martinez-Mayorga, K., Johnson, A.T., Jiao, G.S., and Lindberg, I. (2015) Identification of potent and compartment-selective small molecule furin inhibitors using cell-based assays. Biochem. Pharmacol. 96:107-18 PMID:26003844

Blanco, E.H., Ramos-Molina, B. and Lindberg, I. (2015) Revisiting PC1/3 mutants: dominant-negative effect of endoplasmic reticulum-retained mutants. Endocrinology 156:3625-37. PMID: 26207343

Lindberg, I., Shorter, J. Wiseman, R.L., Chiti, F., Dickey, C.A., and McLean, P.J. (2015) Chaperones in neurodegeneration. J. Neurosci., 35:13853-9. PMID: 26468185

Yamamoto, H., Ramos-Molina, B., Lick, A.N., Prideaux, M., Albornoz, V., Bonewald, L., and Lindberg, I. (2016) Posttranslational processing of FGF23 in osteocytes during the osteoblast to osteocyte transition. Bone 84:120-130. PMID: 26746780

Jarvela, T., Lam, H.A, Helwig, M., Lorenzen, N., Otzen, D.E., McLean, P.J., Maidment, N.T. and Lindberg, I. (2016) The neural chaperone proSAAS blocks alpha-synuclein fibrillation and neurotoxicity. Proc. Natl. Acad Sci. 113(32):E4708-15. PMID: 27457957 PMID:27457957

Ramos-Molina, B., Martin, M.G., and Lindberg, I. (2016) “PCSK1 variants and human obesity”, vol. Genetics of Monogenic and Syndromic Obesity, in series Progress in Molecular Biology and Translational Science. P. Michael Conn, Ed.; Academic Press. PMID:27288825

Additional Publication Citations

Henrich, S. Lindberg, I., Bode, W., and Than, M.E. (2004) Proprotein convertase models based on the crystal structures of furin and kexin: explanation of their specificity. J. Biomol. Structure 345, 211-27.

Peinado, J.R.*, Laurent, V.*, Lee, S.N., Peng, B.W., Pintar, J.E., Steiner, D.F. and Lindberg, I. (2005) Strain-dependent influences on the hypothalamo-pituitary-adrenal axis profoundly affect the 7B2 null phenotype. (*co-first authors) Endocrinology 146, 3438-44.

Kacprzak, M.M., Than, M.E, Juliano, L., Juliano, M.A., Bode, W., and Lindberg, I. (2005) Mutagenesis of the PC2 substrate binding pocket alters enzyme specificity. J. Biol. Chem. 280, 31850-8.

Lindberg, I. (2005) Balancing risk and recovery. Science 310, 972.

Lee, S.N., Hwang, J.R., and Lindberg, I. (2006) The neuroendocrine protein 7B2 can be inactivated by phosphorylation within the secretory pathway. J. Biol. Chem. 281, 3312-20.

Ozawa A., Cai, Y., and Lindberg I. (2007) Production of bioactive peptides in an in vitro system. Analytical Biochem. 366:182-9.

Lee, S.N., Peng, B., Desjardins, R., Pintar, J.E., Day, R., and Lindberg, I. (2007) Strain-specific steroidal control of pituitary function. J. Endocrinol. 192: 515-25.

Lee, S.N. and Lindberg, I. (2008) 7B2 prevents unfolding and aggregation of prohormone convertase 2. Endocrinology 149: 4116-27.

Farber, C.R., Chitwood, J., Lee, S.N., Verdugo, R., Islas-Trejo, Rincon, A.G., Lindberg, I. and Medrano, J.F. (2008) Overexpression of Scg5 increases enzymatic activity of PCSK2 and is negatively correlated with weight gain in congenic mouse models. BMC Genet. 9:34 .

103. Kudo, H., Liu, J., Roubos, E., Ozawa, A., Panula, P. Martens, G.J.M., and Lindberg, I. (2009) Identification of proSAAS homologs in lower vertebrates: conservation of hydrophobic helices and convertase-inhibiting sequences. Endocrinology 150:1393-9.

Kowalska, D., Liu, J., Appel, J.R., Ozawa, A., Nefzi, A., Mackin, R.B., Houghten, R.A., and Lindberg, I. (2009) Synthetic small molecule prohormone convertase 2 inhibitors. Molecular Pharmacology 75: 617-25.

Ozawa, A., Peinado, J.R., and Lindberg, I. (2010) Modulation of prohormone convertase 1/3 properties using site-directed mutagenesis. Endocrinology 151: 4437-45.

Hoshino, A., Kowalska, D., Jean, F., Lazure, C., and Lindberg, I. (2011) Modulation of PC1/3 activity by self-interaction and substrate binding. Endocrinology, 152:1402-11

Helwig, M., Vivoli, M., Fricker, L.D., and Lindberg I. (2011) Regulation of neuropeptide processing enzymes by catecholamines in endocrine cells. Mol. Pharmacol. 80:304-13. PMID: 21540292

Helwig, M., Lee, S-N., Hwang, J.R., Ozawa, A., Medrano, J.F., and Lindberg, I. (2011) Dynamic modulation of PC2-mediated precursor processing by 7B2. J. Biol. Chem. 286:42504-13. PMID: 22013069

Vivoli, M., Caulfield, T.R., Martínez-Mayorga, K., Johnson, A.T., Jiao, G.-S. and Lindberg, I. (2012) Inhibition of PC1/3 and PC2 by 2,5-dideoxystreptamine derivatives. Mol. Pharmacol. 81(3):440-54. PMID: 22169851

Dasgupta, I.*, Sanglas, L.*, Enghild, J. and Lindberg I. (2012) The neuroendocrine protein 7B2 is an intrinsically disordered protein. (*co-first authors) Biochemistry 51(38):7456-64. PMID:22947085

Pickett, L.A., Yourshaw, M., Chen, Z. Solorzano-Vargas, R.S., Nelson, S.F., Martín, M.G., and Lindberg, I. (2013) Functional consequences of a novel variant of PCSK1. PLoS One 8(1):e55065. doi: 10.1371/journal.pone.0055065. PMID: 23383060; PMCID: PMC3557230

Helwig, M., Hoshino, A., Berridge, C., Lee, S.N., Lorenzen, N., Otzen, D., Eriksen, J., and Lindberg, I. (2013) The neuroendocrine protein 7B2 suppresses neurodegenerative disease-related protein aggregation. J. Biol. Chem. 288:1114–1124. PMID: 23172224

Martín, M.G., Lindberg, I, Solorzano-Vargas, R.S., Wang, J., Avitzur, Y., Bandsma, R., Sokollik, C., Lawrence, S., Pickett, L.A., Chen, Z., Egritas, O., Dalgic, B., Albornoz, V., de Ridder, L., Hulst, J., Gok, F., Aydoğan, A., Al-Hussaini, A., Gok, D.E., Yourshaw, M., Wu, S.V., Cortina, G., Stanford, S., and Georgia, S. (2013) Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other

Hoshino, A., Helwig, M., Rezaei, S., Berridge, C., Eriksen, J.L., and Lindberg, I. (2013) A novel function for proSAAS as an amyloid anti-aggregant in Alzheimer’s disease. J. Neurochem. 128(3):419-30. PMID: 24102330 PMCID: PMC3946950

Prabhu, Y., Blanco, E.H., Liu, M., Peinado, J.R., Wheeler, M., Gekakis, N., Arvan, P. and Lindberg, I. (2014) Defective transport of the obesity mutant PC1/3 N222D contributes to loss of function. Endocrinology 155(7):2391-401 PMID: 24828610

Blanco, E.H., Peinado, J.R, Martin, M.G., and Lindberg, I. (2014) Biochemical and cell biological properties of the human prohormone convertase 1/3 Ser357Gly mutation: a PC1/3 hypermorph. Endocrinology 55(9):3434-47 PMID: 24932808

Research Interests

Diabetes and Obesity:

Diabetes, a disease of glucose misregulation, is increasingly prevalent in the world population; approximately 9.3% of the US population has been diagnosed with this chronic disease, and more than twice as many have diabetes but remain undiagnosed. Obesity, often the prelude to diabetes, occurs even more frequently, with more than one-third of the US population currently considered to be obese. Common genetic variants of the proprotein convertase which controls the production of insulin, PC1/3, are strongly associated with human obesity risk, while rare inactivating variants produce a complex endocrine disease which often includes hyperphagia.

Using neuroendocrine cell lines as well as animal models, we study these variants and mutations in prohormone convertases associated with obesity and endocrine disease, using cell biology and biochemical techniques. We have recently begun work on a project centered on the idea that aberrant peptidergic signaling caused by defective PC1/3-mediated brain peptide synthesis contributes to appetite disorders.


Peptidergic hypothalamic pathways controlling appetite and metabolism


Obesity in a 7B2/PC2 null mouse (left) compared to control mouse (right)

Neurodegenerative Disease:

Alzheimer's disease is a devastating neurodegenerative disease presently affecting as many as 5.1 million Americans; the prevalence of the disease increases radically after age 65. Since the Census Bureau has estimated that the number of people over 65 will increase by 2050 to 88.5 million, Alzheimer’s disease presents a large future public health problem. The second most prevalent neurodegenerative disease is Parkinson’s disease, which presently affects over one million individuals in the United States.

Most neurodegenerative diseases involve defects in protein homeostasis that culminate in the production in excess quantities of cytotoxic aggregated proteins. Alzheimer’s disease involves the aberrant association of certain proteins, such as A-beta and tau, into insoluble formations in brain tissues known as plaques and tangles, while Parkinson’s disease involves the aggregation of a sticky protein known as alpha synuclein into Lewy bodies, the pathological hallmark of Parkinson’s. We have identified two secreted chaperone proteins, proSAAS and 7B2, synthesized predominantly in neural and endocrine cells, which we have shown can block the aggregation of sticky secretory molecules in cell line models.

We are especially interested in the role of these secretory chaperones in blocking the formation of protein aggregates in various neurodegenerative disease. Most recently we have shown that proSAAS can block the cytotoxic action of synuclein aggregates in a primary neuron model of Parkinson’s. This work involves immunohistochemistry (of brain tissue from Alzheimer’s and Parkinson’s patients); behavioral assays; cell culture models, and in vitro biochemistry

The neural chaperone proSAAS colocalizes with alpha synuclein in Lewy bodies.

Clinical Specialty Details

Awards and Affiliations

Professional Society Memberships

  • 1978 ‐ present - Society for Neuroscience
  • 1982 - present - Winter Conference on Brain Research
  • 1985 ‐ present - American Society for Biochemistry and Molecular Biology
  • 2001 ‐ present - The Endocrine Society

Career Development Awards 

  • 1981 - NIH Individual Postdoctoral Fellowship (switched to PRAT)
  • 1981‐1983 - Pharmacology Research Associate Traineeship (PRAT)
  • 1988‐1993 - Research Career Development Award (NIDDK)
  • 1993‐1998 - Research Scientist Development Award (NIDA)
  • 1998‐2003 - Research Scientist Development Award (NIDA) 

Editorial Boards

  • 2000-2005 - Editorial Board Member, Journal of Biological Chemistry
  • 2012-present - Editorial Board Member, Journal of Biological Chemistry

Grants and Contracts

Ongoing Research Support

Opioid Peptide Synthesizing Enzymes - 04/01/88-3/31/17
R56 DA05084-28A1 - I. Lindberg, PI
NIH/NIDA
This grant is to investigate the role of human PCSK1 mutations and polymorphisms in peptide-mediated obesity mechanisms.

The Secretory Chaperone 7B2 as an Endogenous Regulator of Amyloid Pathology - 09/01/14- 4/30/17
R21 AG045741-02 - I. Lindberg, PI
NIH/NIA
This grant is to test the hypothesis that brain 7B2 levels modulate the pathologic aggregation of beta amyloid-derived peptides.

Completed Research Support (Competing NIH applications and other grants)

1/85-12/86
I. Lindberg, PI
“Pharmacologic control of opioid peptide biosynthesis.”
Pharmaceutical Manufacturer’s Association Starter Grant

4/85-11/88
I. Lindberg, PI (30% effort)
“Biosynthesis of enkephalin in the adrenal medulla.”
R01 DK35199‐01

4/88‐3/91
I. Lindberg, PI (30% effort)
ʺOpioid peptide‐synthesizing enzymesʺ
R01 DA05084‐01

7/88-6/93
I. Lindberg, PI (90% salary)
Research Career Development Award
K04 DK 01868 (salary award)

12/88-11/91
I. Lindberg, PI(30% effort)
“Biosynthesis of enkephalin in the adrenal medulla.”
R01 DK 35199‐04

4/91-3/94
I. Lindberg, PI (30% effort)
ʺOpioid peptide‐synthesizing enzymesʺ
R01 DA 05084-04

10/93‐ 9/98
I. Lindberg, PI (75% salary)
Research Scientist Development Award
K02 DA 00204‐01 (salary award)

4/94-3/99
I. Lindberg, PI (30% effort)
ʺOpioid peptide‐synthesizing enzymesʺ
R01 DA 05084-07

7/96‐3/02
I. Lindberg, PI (30% effort)
“Control of peptide hormone biosynthesis by PC2 and 7B2”
R01 DK 49703-01

10/98-9/03
I. Lindberg, PI (75%)
Research Scientist Development Award
K02 DA 00204‐06 (salary award renewal)

4/99‐3/04
I. Lindberg, PI (30% effort)
“Opioid peptide‐synthesizing enzymesʺ
R01 DA 05084-12

4/02-3/07
I. Lindberg, PI (30% effort)
“Control of peptide hormone biosynthesis by PC2 and 7B2”
R01 DK 49703-06

2004
I. Lindberg, PI Gordon Conference support grant
“Proprotein processing, trafficking and secretion”
5R13 DK061936

2004
I. Lindberg, PI NSF Conference Support: received $2,000 for a poster award program for the same Gordon Conference cited above

4/04-3/09
I. Lindberg, PI (30% effort)
“Opioid peptide‐synthesizing enzymesʺ
R01 DA 05084-17

9/02‐8/05
I. Lindberg, PI (20% effort)
“Blockade of anthrax toxin cytotoxicity using furin inhibitors”
R21 AI 053517-01

8/03-8/06
P. Sunkara, PI (5% effort)
“Hexa-D-Arg: a furin inhibitor for anthrax biodefense”
Subcontract, Molecular Therapeutics
SBIR R43 AI 056850

9/04-3/06
S. Pincus, PI (5% effort)
“Furin Inhibition in HIV Disease”
R21 AI 058714-01

3/06‐6/06
I. Lindberg, PI (10% effort)
“Furin as an Anti-Cancer Target”
Louisiana Cancer Research Consortium

6/09- 5/11
I. Lindberg, PI (20% effort)
“Identification of Novel Peptide Hormones”
R21 DK084481-01

9/09- 3/14
I. Lindberg (P.I.) (30% effort)
“Control of peptide hormone biosynthesis by PC2 and 7B2”
R01 DK49703-12

7/09-6/14
I. Lindberg and B. Roth (co-P.I.s) (30% effort)
“De-orphanizing the peptidome”
R01 DA027170-01

Community Service

Treasurer, Greater Baltimore Society for Neuroscience, 2014- present

Professional Activity

National Service

Journal Review

  • 1990- present Ad hoc reviewer, J. Biol. Chem., J. Neurochem., Peptides, J. Neurosci., Analyt. Biochem., FEBS Lett., Protein Eng., Design and Selection, Proc. Natl Acad Sci, Endocrine Rev., Diabetes, Molecular Medicine and Metabolism, Mol. Cell. Endocrinol., J. Endocrinol., Endocrinol, PLoS ONE, Mol. Biol. Cell, Eur. J. Cell Biol., and others
  • 2000-2005 Editorial Board Member,Journal of Biological Chemistry
  • 2012-present Editorial Board Member, Journal of Biological Chemistry

Gordon Conference Service

  • 1998, 2000 Advisory Committee Member, Gordon Conference: Hormonal and Neural Peptide Synthesis
  • 2002 Vice‐Chair, Gordon Conference:Hormonal and Neural Peptide Synthesis
  • 2004 Chair, Gordon Conference: Proprotein Processing, Trafficking, and Secretion
  • 2006-2016 Advisory Committee Member, Gordon Conference:Proprotein Processing, Trafficking, and Secretion

Grant Reviewer, NIH:

  • 1987 Study section reviewer, NLS1
  • 1989, 1997 Study section reviewer, NIDA Biochemistry
  • 1989, 1990 Special emphasis panel member, NIDDK
  • 1991 Study section reviewer, NIMH career awards
  • 1994 Special emphasis panel member, NINDS
  • 1995 Study section reviewer, NLS1
  • 1995, 1996, 1998 Study section and special emphasis panel reviewer, NIDDK
  • 1996, 1997, 2002 Study section reviewer, NLS1
  • 1996-2000 Standing member, Endocrinology study section
  • 1999 Study section reviewer, ACS
  • 2000 NIMH Career Awards study section reviewer
  • 2000-2005 Endocrinology study section reviewer ( about 1 panel per year)
  • 2007-2010 Standing member, Molecular and Cellular Endocrinology study section
  • 2010 Special Emphasis Panel reviewer, NIDDK 2/2010
  • 2011 EUREKA NIH review panel member
  • 2013 SBIR study section, 3/2013
  • 2015 MCE study section ad hoc service 6/2015; SBIR ad hoc service 10/2015
  • 2016 SEP ad hoc service

International Review Service

  • 2002 Finnish National Academy of Sciences Review Panel, Helsinki, Finland
  • 2002, 2009,2016 Canada Research Chairs, College of Reviewers, applicant reviewer
  • 2003 Chair, Finnish National Academy of Sciences Review Panel
  • 2005 Foundation for Scientific Research‐ Flanders, Belgium, grant reviewer
  • 2006 Wellcome Trust grant reviewer
  • 2008-2016 Foundation for Scientific Research‐ Flanders, Belgium, grant reviewer
  • 2011 Medical Research Council (U.K.), grant reviewer
  • 2013,2016 Canadian Institutes of Health, grant reviewer
  • 2014 Danish Agency for Science Technology and Innovation

Lab Techniques and Equipment

Biochemistry and Molecular Biology: expression plasmid construction and mutagenesis; production of recombinant proteins, both in bacteria and in eukaryotic cell culture; protein purification and characterization; Western blotting; HPGPC and HPLC of proteins and peptides; radioimmunoassay and ELISA

Cell biology: Neuroendocrine and neural cell line management; metabolic labeling of cell lines, immunoprecipitation, phosphoimaging; confocal analysis of protein localization; protein turnover; cytotoxicity assays

Animal model work: Alzheimer’s model mice; and 7B2 transgenic and knockout model mice. Mouse breeding and colony management; behavioral analysis of cognition using the Morris water maze; immunohistochemical analysis of brain tissue

Major equipment: Akta Purifier, Shimadzu HPLC, Storm phosphoimager, Molecular Devices 96 well fluorometer

Links of Interest