gklamppa@uchicago.edu

B.A., Biology, Reed College, 1973
Ph.D., Plant Biology, University of Washington, 1980

Research Summary

Our major goal is to understand how the pathway of protein import into chloroplasts is regulated, and elucidate the key components involved and their functional roles. The chloroplast carries out the essential reactions of photosynthesis, and houses an amazing array of biosynthetic pathways required for plant development. The chloroplast contains its own DNA, but ~98% of its proteins are encoded by the nuclear genome and synthesized in the cytosol as precursors that must be imported. We identified a zinc-binding stromal processing peptidase (SPP) that removes targeting signals from nearly all proteins entering the chloroplast, allowing them to achieve their functional conformations. Biochemical and transgenic plant studies demonstrated that SPP has been highly conserved during evolution and is essential for plant survival. Because of its pivotal role during protein import, we are establishing how SPP recognizes its unique precursor substrates, the mechanism underlying cleavage, and how SPP activation is controlled.

To broaden our understanding of the chloroplast import pathway, we developed a novel genetic screen in the model plant Arabidopsis. An important class of mutants revealed that the regulation of protein import is integrated into a nitrogen-dependent metabolic network linked to purine catabolism. Chloroplast development and adaptation to light and abiotic stress are altered in the mutants. These findings have important implications for the timing of leaf senescence and plant productivity that depend on efficient photosynthesis and chloroplast metabolism. Our genetic screen provides a new perspective to identify the decisive factors that regulate chloroplast protein import amid a dynamic, and often challenging, cellular environment.

Selected Publications

Lamppa, G. and Zhong, R.  2013.  Chloroplast stromal processing peptidase.  IN:  Handbook of Proteolytic Enzymes.  Third edition. Eds. N. Rawlings and G. Salvese, Elsevier Ltd, London.  Invited review chapter, pp. 1442-1447.

Zhong, R. Thomspon, J., Otttesen, E., and Lamppa, G.  2010. A forward genetic screen to explore chloroplast protein import in vivo identifies Moco sulfurase, pivotal for ABA and IAA biosynthesis and purine turnover.  Plant J. 63:  44-59. (PubMed)

Ottesen, E., Zhong, R., and Lamppa, G.  2010.  Identification of a chloroplast division mutant coding for ARC6H, an ARC6 homolog that plays a nonredundant role.  Plant Science 178:  114-122.  (ScienceDirect)

Ponpuak, M., Klemba, M., Park, M., Gluzman, I., Lamppa, G. and Goldberg, D. 2007. A role for falcilysin in transit peptide degradation in the Plasmodium falciparum apicoplast. Molecular Microbiol.: 63: 314-334. (PubMed)

Richter, S., Zhong, R. and Lamppa, G. (2005) Function of the stromal processing peptidase in the chloroplast import pathway. (Review) Physiol. Plant. 123: 362-368.

Rudhe, C., Clifton, R., Chew, O., Zeman, K., Richter, R., Lamppa, G., Whelan, J., and
Glaser, E. 2004. Processing of the dual targeted precursor protein of glutathione reductase in mitochondria and chloroplasts. J. Mol. Biol. 343: 639-647. (PubMed)

Jin, R., Richter, S., Zhong, R. and Lamppa, G. K. (2003). "Expression and import of an active cellulase from a thermophilic bacterium into the chloroplast both in vitro and in vivo." Plant Mol Biol 51: 493-507. (PubMed)

Zhong, R., Wan, J., Jin, R. and Lamppa, G. (2003). "A pea antisense gene for the chloroplast stromal processing peptidase yields seedling lethals in Arabidopsis: survivors show defective GFP import in vivo." Plant J 34: 802-12. (PubMed)

Richter, S. and Lamppa, G. K. (2003). "Structural properties of the chloroplast stromal processing peptidase required for its function in transit peptide removal." J Biol Chem 278: 39497-502. (PubMed)

Richter, S. and Lamppa, G. K. (2002). "Determinants for removal and degradation of transit peptides of chloroplast precursor proteins." J Biol Chem 277: 43888-94. (PubMed)

Research Summary

My laboratory is engaged in a long term project to understand how DNA sequence specifies biological form. We are interested not only in the specification of typical form by a typical genome, but also in the effects of variability. Such variability might take the form of genetic variation in a population or intrinsic fluctuations in an individual. These problems touch on issues central to developmental and evolutionary biology, and efforts to solve them have previously led to the development of new branches of mathematics. We consider these issues in the specific context of segment determination in the fruit fly Drosophila melanogaster, but actively seek collaborations with investigators working on other organisms or with pure theoreticians. The starting point for our own investigations are quantitative data on gene expression, extracted from images of confocally scanned fixed or living embryos. We use this numerical information to find parameter sets for specific models of fundamental processes of gene regulation and pattern formation by means of large scale optimization procedures performed on parallel computers. These models may be specified in terms of DNA sequence or be more coarse-grained. They might take the form of a dynamical system, deterministic or stochastic, or simply be a complex but explicit mathematical function. Our goal is to use every tool in the toolbox—wet experiments, statistics, computational science, and mathematics—to solve a well focused scientific problem: how does a fly go from DNA sequence to a fate map of presumptive segments at single cell resolution?

Biosciences Graduate Program Association

• Cell and Molecular Biology
• Ecology & Evolution
• Genetics, Genomics & Systems Biology

Publications

1. Reinitz J, Vakulenko S, Grigoriev D, Weber A. Adaptation, fitness landscape learning and fast evolution. F1000Res. 2019; 8:358. View in: PubMed

2. Ramos AF, Reinitz J. Physical implications of so(2, 1) symmetry in exact solutions for a self-repressing gene. J Chem Phys. 2019 Jul 28; 151(4):041101. View in: PubMed

3. Barr KA, Reinitz J. Correction: A sequence level model of an intact locus predicts the location and function of nonadditive enhancers. PLoS One. 2018; 13(5):e0197211. View in: PubMed

4. Barr KA, Martinez C, Moran JR, Kim AR, Ramos AF, Reinitz J. Synthetic enhancer design by in silico compensatory evolution reveals flexibility and constraint in cis-regulation. BMC Syst Biol. 2017 Nov 29; 11(1):116. View in: PubMed

5. Barr KA, Reinitz J. A sequence level model of an intact locus predicts the location and function of nonadditive enhancers. PLoS One. 2017; 12(7):e0180861. View in: PubMed

6. Hope CM, Rebay I, Reinitz J. DNA Occupancy of Polymerizing Transcription Factors: A Chemical Model of the ETS Family Factor Yan. Biophys J. 2017 Jan 10; 112(1):180-192. View in: PubMed

7. Bertolino E, Reinitz J. The analysis of novel distal Cebpa enhancers and silencers using a transcriptional model reveals the complex regulatory logic of hematopoietic lineage specification. Dev Biol. 2016 May 01; 413(1):128-44. View in: PubMed

8. Lou Z, Reinitz J. Parallel Simulated Annealing Using an Adaptive Resampling Interval. Parallel Comput. 2016 Apr 01; 53:23-31. View in: PubMed

9. Lee U, Skinner JJ, Reinitz J, Rosner MR, Kim EJ. Noise-Driven Phenotypic Heterogeneity with Finite Correlation Time in Clonal Populations. PLoS One. 2015; 10(7):e0132397. View in: PubMed

10. Jiang P, Ludwig MZ, Kreitman M, Reinitz J. Natural variation of the expression pattern of the segmentation gene even-skipped in melanogaster. Dev Biol. 2015 Sep 01; 405(1):173-81. View in: PubMed

11. Ramos AF, Hornos JE, Reinitz J. Gene regulation and noise reduction by coupling of stochastic processes. Phys Rev E Stat Nonlin Soft Matter Phys. 2015 Feb; 91(2):020701. View in: PubMed

12. Grigoriev D, Reinitz J, Vakulenko S, Weber A. Punctuated evolution and robustness in morphogenesis. Biosystems. 2014 Sep; 123:106-13. View in: PubMed

13. Martinez C, Rest JS, Kim AR, Ludwig M, Kreitman M, White K, Reinitz J. Ancestral resurrection of the Drosophila S2E enhancer reveals accessible evolutionary paths through compensatory change. Mol Biol Evol. 2014 Apr; 31(4):903-16. View in: PubMed

14. Lee U, Frankenberger C, Yun J, Bevilacqua E, Caldas C, Chin SF, Rueda OM, Reinitz J, Rosner MR. A prognostic gene signature for metastasis-free survival of triple negative breast cancer patients. PLoS One. 2013; 8(12):e82125. View in: PubMed

15. Surkova S, Myasnikova E, Kozlov KN, Pisarev A, Reinitz J, Samsonova M. Quantitative imaging of gene expression in Drosophila embryos. Cold Spring Harb Protoc. 2013 Jun 01; 2013(6):488-97. View in: PubMed

16. Surkova S, Myasnikova E, Kozlov KN, Pisarev A, Reinitz J, Samsonova M. Preparation of Drosophila embryos for quantitative imaging of gene expression. Cold Spring Harb Protoc. 2013 Jun 01; 2013(6):533-6. View in: PubMed

17. Martinez CA, Barr KA, Kim AR, Reinitz J. A synthetic biology approach to the development of transcriptional regulatory models and custom enhancer design. Methods. 2013 Jul 15; 62(1):91-8. View in: PubMed

18. Kim AR, Martinez C, Ionides J, Ramos AF, Ludwig MZ, Ogawa N, Sharp DH, Reinitz J. Rearrangements of 2.5 kilobases of noncoding DNA from the Drosophila even-skipped locus define predictive rules of genomic cis-regulatory logic. PLoS Genet. 2013; 9(2):e1003243. View in: PubMed

19. Surkova S, Golubkova E. Quantitative dynamics and increased variability of segmentation gene expression in the Drosophila Krüppel and knirps mutants. Dev Biol. 2013 Apr 01; 376(1):99-112. View in: PubMed

20. Jaeger J. Drosophila blastoderm patterning. Curr Opin Genet Dev. 2012 Dec; 22(6):533-41. View in: PubMed

21. Kozlov K, Surkova S, Myasnikova E, Reinitz J, Samsonova M. Modeling of gap gene expression in Drosophila Kruppel mutants. PLoS Comput Biol. 2012; 8(8):e1002635. View in: PubMed

22. Reinitz J. Turing centenary: Pattern formation. Nature. 2012 Feb 22; 482(7386):464. View in: PubMed

23. Gursky VV, Panok L, Myasnikova EM. Mechanisms of gap gene expression canalization in the Drosophila blastoderm. BMC Syst Biol. 2011; 5:118. View in: PubMed

24. Surkova SIu, Gurskii VV, Reinitz J, Samsonova MG. [Studies of stability mechanisms of early embryonal development of fruit fly Drosophila]. Ontogenez. 2011 Jan-Feb; 42(1):3-19. View in: PubMed

25. Vakulenko S. Size regulation in the segmentation of Drosophila: interacting interfaces between localized domains of gene expression ensure robust spatial patterning. Phys Rev Lett. 2009 Oct 16; 103(16):168102. View in: PubMed

26. Canalization of gene expression in the Drosophila blastoderm by gap gene cross regulation. PLoS Biol. 2009 Mar; 7(3):e1000049. View in: PubMed

27. Kozlov KN, Myasnikova E, Samsonova AA, Surkova S, Reinitz J, Samsonova M. GCPReg package for registration of the segmentation gene expression data in Drosophila. Fly (Austin). 2009 Apr-Jun; 3(2):151-6. View in: PubMed

28. Surkova SY, Myasnikova EM, Kozlov KN, Samsonova AA, Reinitz J, Samsonova MG. Methods for Acquisition of Quantitative Data from Confocal Images of Gene Expression in situ. Cell tissue biol. 2008 Apr; 2(2):200-215. View in: PubMed

29. Canalization of gene expression and domain shifts in the Drosophila blastoderm by dynamical attractors. PLoS Comput Biol. 2009 Mar; 5(3):e1000303. View in: PubMed

30. Myasnikova E, Surkova S, Panok L, Samsonova M, Reinitz J. Estimation of errors introduced by confocal imaging into the data on segmentation gene expression in Drosophila. Bioinformatics. 2009 Feb 01; 25(3):346-52. View in: PubMed

31. Pisarev A, Poustelnikova E, Samsonova M, Reinitz J. FlyEx, the quantitative atlas on segmentation gene expression at cellular resolution. Nucleic Acids Res. 2009 Jan; 37(Database issue):D560-6. View in: PubMed

32. Surkova S, Myasnikova E, Janssens H, Kozlov KN, Samsonova AA, Reinitz J, Samsonova M. Pipeline for acquisition of quantitative data on segmentation gene expression from confocal images. Fly (Austin). 2008 Mar-Apr; 2(2):58-66. View in: PubMed

33. Surkova SIu, Miasnikova EM, Kozlov KN, Samsonova AA, Reinitz J, Samsonova MG. [Methods for acquisition of quantitative from confocal images of gene expression in situ]. Tsitologiia. 2008; 50(4):352-69. View in: PubMed

34. Gurskii VV, Kozlov KN, Samsonov AM, Reinitz J. [A model with asymptotically stable dynamics for the network of Drosophila gap genes]. Biofizika. 2008 Mar-Apr; 53(2):235-49. View in: PubMed

35. Surkova S, Kosman D, Kozlov K. Characterization of the Drosophila segment determination morphome. Dev Biol. 2008 Jan 15; 313(2):844-62. View in: PubMed

36. Wu YF, Myasnikova E, Reinitz J. Master equation simulation analysis of immunostained Bicoid morphogen gradient. BMC Syst Biol. 2007 Nov 16; 1:52. View in: PubMed

37. Reinitz J. Developmental biology: a ten per cent solution. Nature. 2007 Jul 26; 448(7152):420-1. View in: PubMed

38. Jaeger J, Sharp DH, Reinitz J. Known maternal gradients are not sufficient for the establishment of gap domains in Drosophila melanogaster. Mech Dev. 2007 Feb; 124(2):108-28. View in: PubMed

39. Jaeger J, Reinitz J. On the dynamic nature of positional information. Bioessays. 2006 Nov; 28(11):1102-11. View in: PubMed

40. Janssens H, Hou S, Jaeger J, Kim AR, Myasnikova E, Sharp D, Reinitz J. Quantitative and predictive model of transcriptional control of the Drosophila melanogaster even skipped gene. Nat Genet. 2006 Oct; 38(10):1159-65. View in: PubMed

41. Perkins TJ, Jaeger J, Reinitz J, Glass L. Reverse engineering the gap gene network of Drosophila melanogaster. PLoS Comput Biol. 2006 May; 2(5):e51. View in: PubMed

42. Lebrecht D, Foehr M, Smith E, Lopes FJ, Vanario-Alonso CE, Reinitz J, Burz DS, Hanes SD. Bicoid cooperative DNA binding is critical for embryonic patterning in Drosophila. Proc Natl Acad Sci U S A. 2005 Sep 13; 102(37):13176-81. View in: PubMed

43. Janssens H, Kosman D, Vanario-Alonso CE, Jaeger J, Samsonova M, Reinitz J. A high-throughput method for quantifying gene expression data from early Drosophila embryos. Dev Genes Evol. 2005 Jul; 215(7):374-81. View in: PubMed

44. Myasnikova E, Samsonova M, Kosman D, Reinitz J. Removal of background signal from in situ data on the expression of segmentation genes in Drosophila. Dev Genes Evol. 2005 Jun; 215(6):320-6. View in: PubMed

45. Jaeger J, Blagov M, Kosman D, Kozlov KN. Dynamical analysis of regulatory interactions in the gap gene system of Drosophila melanogaster. Genetics. 2004 Aug; 167(4):1721-37. View in: PubMed

46. Jaeger J, Surkova S, Blagov M, Janssens H, Kosman D, Kozlov KN. Dynamic control of positional information in the early Drosophila embryo. Nature. 2004 Jul 15; 430(6997):368-71. View in: PubMed

47. Poustelnikova E, Pisarev A, Blagov M, Samsonova M, Reinitz J. A database for management of gene expression data in situ. Bioinformatics. 2004 Sep 22; 20(14):2212-21. View in: PubMed

48. Gursky VV, Reinitz J, Samsonov AM. How gap genes make their domains: An analytical study based on data driven approximations. Chaos. 2001 Mar; 11(1):132-141. View in: PubMed

49. Myasnikova E, Samsonova A, Samsonova M, Reinitz J. Support vector regression applied to the determination of the developmental age of a Drosophila embryo from its segmentation gene expression patterns. Bioinformatics. 2002; 18 Suppl 1:S87-95. View in: PubMed

50. Holloway DM, Reinitz J, Spirov A, Vanario-Alonso CE. Sharp borders from fuzzy gradients. Trends Genet. 2002 Aug; 18(8):385-7. View in: PubMed

51. Kozlov K, Myasnikova E, Pisarev A, Samsonova M, Reinitz J. A method for two-dimensional registration and construction of the two-dimensional atlas of gene expression patterns in situ. In Silico Biol. 2002; 2(2):125-41. View in: PubMed

52. Aizenberg I, Myasnikova E, Samsonova M, Reinitz J. Temporal classification of Drosophila segmentation gene expression patterns by the multi-valued neural recognition method. Math Biosci. 2002 Mar; 176(1):145-59. View in: PubMed

53. Wu X, Vasisht V, Kosman D, Reinitz J, Small S. Thoracic patterning by the Drosophila gap gene hunchback. Dev Biol. 2001 Sep 01; 237(1):79-92. View in: PubMed

54. Myasnikova E, Samsonova A, Kozlov K, Samsonova M, Reinitz J. Registration of the expression patterns of Drosophila segmentation genes by two independent methods. Bioinformatics. 2001 Jan; 17(1):3-12. View in: PubMed

55. Myasnikova EM, Kosman D, Reinitz J, Samsonova MG. Spatio-temporal registration of the expression patterns of Drosophila segmentation genes. Proc Int Conf Intell Syst Mol Biol. 1999; 195-201. View in: PubMed

56. Spirov AV, Bowler T, Reinitz J. HOX Pro: a specialized database for clusters and networks of homeobox genes. Nucleic Acids Res. 2000 Jan 01; 28(1):337-40. View in: PubMed

57. Hewitt GF, Strunk BS, Margulies C, Priputin T, Wang XD, Amey R, Pabst BA, Kosman D, Reinitz J, Arnosti DN. Transcriptional repression by the Drosophila giant protein: cis element positioning provides an alternative means of interpreting an effector gradient. Development. 1999 Mar; 126(6):1201-10. View in: PubMed

58. Sharp DH, Reinitz J. Prediction of mutant expression patterns using gene circuits. Biosystems. 1998 Jun-Jul; 47(1-2):79-90. View in: PubMed

59. Reinitz J, Kosman D, Vanario-Alonso CE, Sharp DH. Stripe forming architecture of the gap gene system. Dev Genet. 1998; 23(1):11-27. View in: PubMed

60. Kosman D, Reinitz J, Sharp DH. Automated assay of gene expression at cellular resolution. Pac Symp Biocomput. 1998; 6-17. View in: PubMed

61. Kosman D, Small S, Reinitz J. Rapid preparation of a panel of polyclonal antibodies to Drosophila segmentation proteins. Dev Genes Evol. 1998 Jul; 208(5):290-4. View in: PubMed

62. Reinitz J, Mjolsness E, Sharp DH. Model for cooperative control of positional information in Drosophila by bicoid and maternal hunchback. J Exp Zool. 1995 Jan 01; 271(1):47-56. View in: PubMed

63. Wright LW, Lichter JB, Reinitz J, Shifman MA, Kidd KK, Miller PL. Computer-assisted restriction mapping: an integrated approach to handling experimental uncertainty. Comput Appl Biosci. 1994 Jul; 10(4):435-42. View in: PubMed

64. Reinitz J, Sharp DH. Mechanism of eve stripe formation. Mech Dev. 1995 Jan; 49(1-2):133-58. View in: PubMed

65. Reinitz J, Vaisnys JR. Theoretical and experimental analysis of the phage lambda genetic switch implies missing levels of co-operativity. J Theor Biol. 1990 Aug 09; 145(3):295-318. View in: PubMed

66. Reinitz J, Levine M. Control of the initiation of homeotic gene expression by the gap genes giant and tailless in Drosophila. Dev Biol. 1990 Jul; 140(1):57-72. View in: PubMed

67. Mjolsness E, Sharp DH, Reinitz J. A connectionist model of development. J Theor Biol. 1991 Oct 21; 152(4):429-53. View in: PubMed

ewt1@uchicago.edu

B.A., Physics and Chemistry University of Toronto, 1952
M.Sc., Physical Chemistry McMaster University, 1955
Ph.D., Biophysics The University of Chicago, 1957

Research Summary

We study the mechanism of molecular motors, myosin with actin and kinesin with microtubules. The objective is to show how the steps in the kinetic mechanism determine the structural changes which produce force and motion. To disect the steps in the system mutant kinesins, expressed in bacteria, are studied in which a step in the mechanism is blocked. The results are correlated with the structure of the protein and its motility properties determined by in vitro assay.

Selected Publications

Ma, Y. Z. and Taylor, E. W. (1997). "Interacting head mechanism of microtubule-kinesin ATPase." J Biol Chem 272: 724-30. (PubMed)

Ma, Y. Z. and Taylor, E. W. (1997). "Kinetic mechanism of a monomeric kinesin construct." J Biol Chem 272: 717-23. (PubMed)

Pechatnikova, E. and Taylor, E. W. (1997). "Kinetic mechanism of monomeric non-claret disjunctional protein (Ncd) ATPase." J Biol Chem 272: 30735-40. (PubMed)

bs19@uchicago.edu

B.S., Chemistry, City College of New York, 1947
Magna cum laude Ph.D., Biochemistry and Immunology, California Institute of Technology, 1950

Research Summary

During the period from 1960 until about 2008 this laboratory was involved in studies on DNA repair and on the mechanism of mutation, particularly attempting to understand the role of polymerases and editing nucleases.

Selected Publications

Strauss B. PubMed, The New York Times, and The Chicago Tribune as Tools for Teaching Genetics. Genetics. 2005 171:1449-1454. (PubMed)

Strauss B. ROSY and JIM: The Mystery of THE DOUBLE HELIX. Perspect Biol Med. 2004 Summer;47(3):443-8. (PubMed)

Strauss BS. The "A" rule revisited: polymerases as determinants of mutational specificity. DNA Repair (Amst). 2002 Feb 28;1(2):125-35. (PubMed)

Sagher D, Karrison T, Schwartz JL, Larson R, Meier P, Strauss B. Low O6-alkylguanine DNA alkyltransferase activity in the peripheral blood lymphocytes of patients with therapy-related acute nonlymphocytic leukemia. Cancer Res. 1988 Jun 1;48(11):3084-9. (PubMed)

Sagher D, Strauss B. Insertion of nucleotides opposite apurinic/apyrimidinic sites in deoxyribonucleic acid during in vitro synthesis: uniqueness of adenine nucleotides. Biochemistry. 1983 Sep 13;22(19):4518-26. (PubMed)

Higgins NP, Kato K, Strauss B. A model for replication repair in mammalian cells. J Mol Biol. 1976 Mar 5;101(3):417-25. (PubMed)

Pauli RM, Strauss BS. Proliferation of human peripheral lymphocytes. Characteristics of cells once stimulated or re-stimulated by concanavalin A. Exp Cell Res. 1973 Dec;82(2):357-66. (PubMed)

Tsuda Y, Strauss BS. A deoxyribonuclease reaction requiring nucleoside di- or triphosphates. Biochemistry. 1964 Nov;3:1678-84. (PubMed)

Okubo S, Stodolsky M, Bott K, Strauss BS. Separation of the transforming and viral deoxyribonucleic acids of a transducing bacteriophage of Bacillus subtilis. Proc Natl Acad Sci U S A. 1963 Oct;50:679-86. (PubMed)

Strauss BS. Differential destruction of the transforming activity of damaged deoxyribonucleic acid by a bacterial enzyme. Proc Natl Acad Sci U S A. 1962 Sep 15;48:1670-5. (PubMed)

Strauss, B.S. An Outline of Chemical Genetics. 1960. W.B. Saunders. Co., Philadelphia. (books.google.com)

tsteck@bsd.uchicago.edu

B.S., Lawrence College, 1960
M.D., Harvard Medical School, 1964

Research Summary

My long-term research interest is in membrane biochemistry. Over the years, I have studied the molecular organization of the human red cell membrane and several aspects of the cell biology of the ameba, Dictyostelium discoideum. In addition, the disposition of cell cholesterol has been a recurrent focus. We are currently investigating cellular cholesterol homeostasis: how cells sense their need for this essential plasma membrane lipid and make appropriate adjustments to keep it in balance. We suggest that cells gauge the magnitude of the bulk pool of cholesterol in the plasma membrane by sensing the high activity of the cholesterol in excess of phospholipids. This active excess sets the size of the sterol pool in the endoplasmic reticulum and mitochondria through the flow of cholesterol between the cell surface and intracellular membranes. The endoplasmic reticulum pool then sets the level of activity of several regulatory elements in its membrane that mediate sterol homeostasis while the mitochondria convert cholesterol to oxysterols that serve as messengers of cholesterol excess. The elements of this cholesterol sensing system and how it can be manipulated are under investigation.

Selected Publications

Lange, Y. and Steck, T.L. (2016). Active membrane cholesterol as a physiological effector. Chem Phys Lipids. pii: S0009-3084(16)30015-9. doi: 10.1016/j.chemphyslip.2016.02.003. (PubMed)

Czyz DM, Potluri LP, Jain-Gupta N, Riley SP, Martinez JJ, Steck TL, Crosson S, Shuman HA, Gabay JE. Host-directed antimicrobial drugs with broad-spectrum efficacy against intracellular bacterial pathogens. MBio. 2014; 5(4):e01534-14. (PubMed)

Lange Y, Ye J, Steck TL. Essentially all excess fibroblast cholesterol moves from plasma membranes to intracellular compartments. PLoS One. 2014; 9(7):e98482. (PubMed)

Tietjen GT, Gong Z, Chen CH, Vargas E, Crooks JE, Cao KD, Heffern CT, Henderson JM, Meron M, Lin B, Roux B, Schlossman ML, Steck TL, Lee KY, Adams EJ. Molecular mechanism for differential recognition of membrane phosphatidylserine by the immune regulatory receptor Tim4. Proc Natl Acad Sci U S A. 2014 Apr 15; 111(15):E1463-72. (PubMed)

Lange Y, Tabei SM, Ye J, Steck TL. Stability and stoichiometry of bilayer phospholipid-cholesterol complexes: relationship to cellular sterol distribution and homeostasis. Biochemistry. 2013 Oct 8; 52(40):6950-9. (PubMed)

Lange, Y., Ye, J., and Steck, T.L. (2012) Activation mobilizes the cholesterol in the late endosomes-lysosomes of Niemann Pick Type C cells. PLoS One 7, e30051. (PubMed)

Steck, T.L., and Lange, Y. (2010) Cell cholesterol homeostasis: Mediation by active cholesterol. Trends in Cell Biology 20, 680-687. (PubMed)

Lange, Y., Ye, J., Duban, M.-E., and Steck, T. L. (2009) Activation of Membrane Cholesterol by 63 Amphipaths. Biochemistry 48, 8505-8515. (PubMed)

Lange, Y., Steck, T. L., Ye, J., Lanier, M. H., Molugu, V., and Ory, D. (2009) Regulation of fibroblast mitochondrial 27-hydroxycholesterol production by active plasma membrane cholesterol. Journal of Lipid Research 50, 1881-1888. (PubMed)

Lange, Y., and Steck, T.L. (2008). Cholesterol homeostasis and the escape tendency (activity) of plasma membrane cholesterol. Prog Lipid Res 47, 319-332. (PubMed)

Lange, Y., Ory, D.S., Ye, J., Lanier, M.H., Hsu, F.-F., and Steck, T.L. (2008). Effectors of Rapid Homeostatic Responses of Endoplasmic Reticulum Cholesterol and 3-Hydroxy-3-methylglutaryl-CoA Reductase. J Biol Chem 283, 1445-1455. (PubMed)

Ratajczak, M.K., Ko, Y.T.C., Lange, Y., Steck, T.L., and Lee, K.Y.C. (2007). Cholesterol Displacement from Membrane Phospholipids by Hexadecanol. Biophys J 93, 2038-2047. (PubMed)

Lange Y, Ye J, Steck TL. (2007). Scrambling of phospholipids activates red cell membrane cholesterol. Biochemistry. 46(8):2233-8. (PubMed)

tema@uchicago.edu

B.S., Biochemistry, University of Adelaide, 1961
Ph.D., Biochemistry, University of Cambridge, 1966

Research Summary

Current research continues to be centered on basic mechanisms of gene expression, particularly in regard to nuclear structure and RNA synthesis and processing; in this regard we have studied the influence of viruses on the nuclear protein antigens of autoimmune disease. The reorganization of these nuclear antigens during normal development and during apoptosis has also been addressed in collaboration with several European laboratories. Currently the proteins directly involved in RNA transcription elongation are under study, and this has led to an active collaboration on the relationship of transcription to somatic hypermutation of Ig genes with Ursula Storb (see recent publications).

Our recent discovery of a novel stomach protein, expressed only in the lumenal surface epithelial cells, has led us to initiate a study of this gene in humans and mice. We have raised high-titer antibodies to the protein and used immuno-electron microscopy to localize it to secretion granules of mucosal epithelial cells. Our current studies have demonstrated that it has growth factor activity; the additional possibility that it can serve as a precursor of bioactive peptides with a role in innate immunity in the stomach is being explored. Given the need for rapid replacement of gastric epithelial cells as a result of the acid environment, mechanical damage and possible bacterial infiltration it is likely that this factor is important in the maintenance and restitution of the stomach epithelium. We propose to analyze the mechanism of gastric epithelial cell growth stimulation and study the consequences of a knockout of this gene in mice.

Selected Publications

Toback, F. G., Walsh-Reitz, M. M., Musch, M. W., Chang, E. B., Del Valle, J., Ren, H., Huang, E. and Martin, T. E. (2003). "Peptide fragments of AMP-18, a novel secreted gastric antrum mucosal protein, are mitogenic and motogenic." Am J Physiol Gastrointest Liver Physiol 285: G344-53. (PubMed)

Vazquez-Nin, G. H., Echeverria, O. M., Ortiz, R., Scassellati, C., Martin, T. E., Ubaldo, E. and Fakan, S. (2003). "Fine Structural Cytochemical Analysis of Homologous Chromosome Recognition, Alignment, and Pairing in Guinea Pig Spermatogonia and Spermatocytes." Biol Reprod. (PubMed)

Kim, N., Martin, T. E., Simon, M. C. and Storb, U. (2003). "The transcription factor Spi-B is not required for somatic hypermutation." Mol Immunol 39: 577-83. (PubMed)

Martin, T. E., Powell, C. T., Wang, Z., Bhattacharyya, S., Walsh-Reitz, M. M., Agarwal, K. andToback, F. G. (2003). "A novel mitogenic protein that is highly expressed in cells of the gastric antrum mucosa." Am J Physiol Gastrointest Liver Physiol 285: G332-43. (PubMed)

Michael, N., Martin, T. E., Nicolae, D., Kim, N., Padjen, K., Zhan, P., Nguyen, H., Pinkert, C. and Storb, U. (2002). "Effects of sequence and structure on the hypermutability of immunoglobulin genes." Immunity 16: 123-34. (PubMed)

Soldani, C., Bottone, M. G., Biggiogera, M., Alpini, C., Scovassi, A. I., Martin, T. and Pellicciari, C. (2002). "Nuclear localization of phosphorylated c-Myc protein in human tumor cells." Eur J Histochem 46: 377-80. (PubMed)

Pellicciari, C., Bottone, M. G., Scovassi, A. I., Martin, T. E. and Biggiogera, M. (2000). "Rearrangement of nuclear ribonucleoproteins and extrusion of nucleolus-like bodies during apoptosis induced by hypertonic stress." Eur J Histochem 44: 247-54. (PubMed)

am29@uchicago.edu

B.S., Biology, Spring Hill College, 1958
Ph.D., Biology, Johns Hopkins University, 1962

Research Summary

My laboratory is investigating the genetic control of key developmental events, using Drosophila melanogaster as our organism. Our approach has been to identify genetically as many of the components of the process as possible, attempt to order these elements through genetic interactions, and then move to a molecular analysis of the central genes in the process. Since becoming Emeritus, I have concentrated on a set of mutations that affect the mitochondrial derivative during spermiogenesis. In wild-type flies all the mitochondria in each spermatid fuse into two mitochondria which interweave with each other in the Nebenkern. During growth of the axoneme the two mitochondria unwind from each other and extend along the growing axoneme. Mutations which interfere with either the fusion process or the extension process are sterile. Efforts are in progress to identify the molecular processes involved in more than 25 different mutations affecting these events. I also continue a collaboration with Dr. Yuzo Niki in Japan to develop protocols for the culture of ovarian germline stem cells. We have shown that cultured cells can repopulate the germline and produce functional eggs. We currently have stable cultures composed of mixed populations of somatic and germline cells. If gene replacement methods can be developed for germline cells in these cultures, these cells could be the source for genetically modified germlines in flies.

Selected Publications

Srinivasan, S., Mahowald, A. P. and Fuller, M. T. 2012. The receptor phosphatase Lar regulates adhesion between Drosophila male germline stem cells and the niche. Development 139: 1381-1390. (PubMed)

Lu, W., Casanueva, M. O., Mahowald, A. P., Kato, M., Lauterbach, D., and Ferguson, E. L. 2012. Niche-associated acgivation of rac promotes the asymmetric division of Drosophila female germline stem cells. PLoS Biol. 10: e1001357. (PubMed)

Chatterjuee, N., Rollins, J., Mahowald, A. P., and Bazinet, C. 2011. Neurotransmitter Transporter-Like: a male germline-specific SLC6 transporter required for Drosophila spermiogenesis. PLoS ONE 6: e16275. (PubMed)

Yamashita, Y. M., Mahowald, A. P., Perlin, J. R., and Fuller, M. T. 2007. Asymmetric inheritance of mother versus daughter centrosome in stem cell division. Science 315:518-21. (PubMed)

Niki, Y., Yamaguchi, T., and Mahowald, A. P. 2006. Establishment of stable cell lines of Drosophila germline stem cells. Proc. Natl. Acad. Sci. USA 103: 16325-16330. (PubMed)

Tazuke, S. I., C. Schulz, L. Gilboa, A. P. Mahowald, A. Guichet, A. Ephrussi, C. G. Wood, R. Lehmann and M. T. Fuller. 2002. A germ line specfic gap junction protein is required for survival of differentiating early germ cells. Development 129: 2529-2539.(PubMed)

Niki, Y. and Mahowald, A. P. (2003). "Ovarian cystocytes can repopulate the embryonic germ line and produce functional gametes." Proc Natl Acad Sci U S A 100: 14042-5. (PubMed)

Mahowald, A. P. (2001). "Assembly of the Drosophila germ plasm." Int Rev Cytol 203: 187-213. (PubMed)

rh01@uchicago.edu

Research Summary

Our current program is focused on two sets of problems: heterocyst differentiation in filamentous cyanobacteria and the properties of the enzyme acetyl-CoA carboxylase (ACC).

The cyanobacterium Anabaena grows in very long chains, the cells carrying out green plant photosynthesis. When faced with a shortage of fixed nitrogen, specialized cells called heterocysts differentiate at regular intervals along each filament, usually separated by about ten vegetative cells. The heterocysts do not divide. They quit doing carbon fixation but instead create an anaerobic environment for nitrogen fixation. The sequenced genome of Anabaena contains about 7000 genes, of which about 1500 are expressed differentially during heterocyst development. This program involves a cascade of transcription that involves at the start a factor called HetR, which we discovered long ago. This protein is studied now by many labs. One of my alumni identified the palindromic sequence in the genome to which it binds and another found a small peptide that prevents that binding. We have crystallized HetR from many species of cyanobacteria and solved the X-ray structure of one from the thermophile Fischerella. We have also solved the structure of complexes of the HetR dimer with several palindromic DNA sequences, ones containing 21, 23 and 25 base pairs. This work is continuing, in collaboration with Andrzej Joachimiak at the Argonne National Laboratory, Michelle Ye in China, and Sean Callahan in Hawaii. We also follow single heterocyst differentiation using confocal fluorescence microscopy. The current program is pursued by postdocs Shan Ke and Amin Nasser.

The program on ACC is directed by Research Associate Piotr Gornicki, who was the first to purify the two wheat isozymes (chloroplast and cytoplasmic) and to clone their genes. We used their respective cDNAs in recombinant yeast to study the basis of herbicide sensitivity and found a single amino acid responsible for the resistance phenotype. The recombinant yeast system was then exploited to study the ACCs of parasites and eventually the two isoforms of human ACC. Currently, the lab is working on the human enzymes to determine possible targets for drugs to treat obesity.

Selected Publications

Youngchang Kim, Grazyna Joachimiak, Zi Ye, T. Andrew Binkowski, Rongguang Zhang, Piotr Gornicki, Sean M. Callahan, Wolfgang R. Hess, Robert Haselkorn and Andrzej Joachimiak. Structure of the Transcription Factor HetR Required for Heterocyst Differentiation in Cyanobacteria. Proc. Natl Acad. Sci USA 108: 10109-10114 (2011). (PubMed)

J. Marjanovic, D. Chalupska, C. Patenode, A. Coster, E. Arnold, A. Ye, G. Anesi, R.Y.Lu, I. Okun, S. Tkachenko, R. Haselkorn and P. Gornicki. A recombinant yeast screen for new inhibitors of human ACC2 identifies potential drugs to treat obesity. Proc. Nat. Acad. Sci. USA 107: 9093-9098 (2010). (PubMed)

Liu, W., Harrison, D.K., Chalupska, D., Gornicki, P., O’Donnell, C.C., Adkins, S.W., Haselkorn, R. and Williams, R.R. Single-site mutations in the carboxyltransferase domain of plastid acetyl-CoA carboxylase confer resistance to grass-specific herbicides. Proc. Natl Acad Sci. USA 104: 3627-3632 (2007). (PubMed)

Rouhaiainen,L., Vakkilainen, T., Siemer, B.L., Buikema, W., Haselkorn, R., and Sivonen, K. Genes coding for the synthesis of hepatotoxic heptapeptides (Microcystins) in the cyanobacterium Anabaena strain 90. App. Env. Micro. 70: 686-692 (2004). (PubMed)