Louis Simchowitz, M.D., M.B.A. : NIDDK

Louis Simchowitz, M.D., M.B.A.


Office of Fellow Recruitment and Career Development,

Director

ODIR
DIVISION INTRAMURAL RESEARCH
NIDDK, National Institutes of Health
Building 12A, Room 3011
12 South Dr.
Bethesda, MD 20892-5632
Tel: 301-451-9808
Fax: 301-402-7461
Email: ls347f@nih.gov

Research Website:


Education / Previous Training and Experience:
B.S., The City College of New York, 1966
M.D., New York University School of Medicine, 1970
M.B.A., Washington University - Olin School of Business, 1999


Research Statement:

Obesity is a global public health problem of epidemic proportions. It is the source of considerable morbidity and early mortality in the U.S. and is associated with increased risk of diabetes, hypertension, cardiovascular disease, and cancer to name a few. All segments of the population are affected and the burden to society, in terms of general well-being and healthcare costs, is tremendous.

In recent years, new and evolving concepts have emerged regarding obesity as a chronic endocrine disorder of inflammation. Moreover, a small, but growing body of evidence both in animals and in man indicates that obesity per se alters the profile of a constellation of genes and that at least some of these changes in biomarkers of inflammation and gene expression can be reversed by weight loss. The data in humans is rather scant, with just a handful of articles on this subject in the current literature.

In a series of clinical protocols, we propose to extend the early and evolving work in humans by testing and reconfirming the idea that a particular set of genes is activated (or deactivated) in overweight and in obese subjects using standard microarray techniques on samples of subcutaneous adipose tissue derived from biopsies. In addition, we will broaden and extend this work by studying the local adipose tissue microenvironment in vivo by means of a microdialysis procedure, a minimally invasive technique that allows the serial determination of components of the extracellular fluid under physiological conditions. The role of a number of adipokines (such as leptin and adiponectin) and inflammatory mediators/cytokines (e.g., TNF-á, IL-6, and eicosanoids such as Prostaglandin E2, Lipoxin A4, and Leukotriene B4) will be analyzed using sensitive Liquid Chromatography-Tandem Mass Spectrometry and ELISA methods.

The experimental design incorporates two basic objectives: (a) Comparison of Normal vs. Overweight and Obese subjects at Baseline and (b) Correlation of changes in Overweight and Obese patients over time as they lose weight through a calorie-restricted diet. To these ends, 30 Normal Controls (BMI 19.0 – 24.9), 30 Overweight Subjects (BMI 25.0 – 29.9), and 50 Obese Subjects (BMI 30.0-40.0) will be enrolled. Baseline studies, to be obtained on all participants include: routine and specialized blood tests, anthropometric indices, body composition by air-displacement plethysmography, indirect calorimetry, hyperinsulinemic clamp measurements as an index of insulin sensitivity, subcutaneous adipose tissue microdialysis procedures to sample the local microenvironment for various adipokines, cytokines, and eicosanoid mediators of inflammation, and subcutaneous adipose tissue biopsy for analysis of gene expression using standard microarray techniques. These procedures will require an overnight hospital admission to the Clinical Center.

Overweight and Obese subjects will then be prescribed a calorie-restricted diet and followed for one year. They will undergo the same repeat studies and procedures outlined above at regular, 3-month intervals so as to assess serial changes in the various parameters and to provide correlative data with the degree and rate of weight loss achieved.

Taken together, these studies should shed light and provide fundamental insights into the nature of the altered gene expression and release of inflammatory cytokines and other mediators that characterize the overweight/obese state and the dynamic series of events that take place when dietary intervention leads to weight loss. It is anticipated that a number of these changes will relate to macrophages and known inflammatory markers though doubtless there are other important leads yet to be discovered. Thus, our hope is that such studies will ultimately lead to the identification of novel genes that underlie the important metabolic derangements associated with obesity and their response to different treatment modalities.



Selected Publications:

Dale WE Textor JA Mercer RW Simchowitz L Expression and characterization of the human erythrocyte anion exchanger in a baculovirus/Sf-9 cell system. Protein Expr Purif(7): 1-11, 1996. [Full Text/Abstract]

Simchowitz L Fiore S Serhan CN Carrier-mediated transport of lipoxin A4 in human neutrophils. Am J Physiol(267): C1525-34, 1994. [Full Text/Abstract]

Simchowitz L Textor JA Cragoe EJ Jr Cell volume regulation in human neutrophils: 2-(aminomethyl)phenols as Cl- channel inhibitors. Am J Physiol (265): C143-55, 1993. [Full Text/Abstract]

Porras-Reyes BH Lewis WH Roman J Simchowitz L Mustoe TA Enhancement of wound healing by the alkaloid taspine defining mechanism of action. Proc Soc Exp Biol Med (203): 18-25, 1993. [Full Text/Abstract]

Simchowitz L Vogt SK Substrate and inhibitor specificity of the lactate carrier of human neutrophils. J Membr Biol (131): 23-34, 1993. [Full Text/Abstract]

Stoddard JS Steinbach JH Simchowitz L Whole cell Cl- currents in human neutrophils induced by cell swelling. Am J Physiol (265): C156-65, 1993. [Full Text/Abstract]

Simchowitz L Kleyman TR Cragoe EJ An overview of the structure-activity relations in the amiloride series. In: Amiloride and Its Analogs: Unique Cation Transport Inhibitors. Cragoe EJ Kleyman TR Simchowitz L, editors. VCH Publishers, 1992. pp.9-24

Simchowitz L Textor JA Lactic acid secretion by human neutrophils. Evidence for an H+ + lactate- cotransport system. J Gen Physiol (100): 341-67, 1992. [Full Text/Abstract]

Dale WE Simchowitz L Na+/H+ exchange in blood cells. In: Amiloride and Its Analogs: Unique Cation Transport Inhibitors. Cragoe Ej Kleyman TR Simchowitz L, editors. VCH Publishers, 1992. pp.79-96

Simchowitz L Davis AO Internal alkalinization by reversal of anion exchange in human neutrophils: regulation of transport by pH. Am J Physiol (260): C132-42, 1991. [Full Text/Abstract]

Dale WE Simchowitz L The role of Na(+)-Ca2+ exchange in human neutrophil function. Ann N Y Acad Sci (639): 616-30, 1991. [Full Text/Abstract]

Simchowitz L Textor JA Vogt SK Use of tributyltin to probe contribution of Cl(-)-HCO3- exchange to regulation of steady-state pHi in human neutrophils. Am J Physiol (261): C906-15, 1991. [Full Text/Abstract]

Simchowitz L Foy MA Cragoe EJ Jr A role for Na+/Ca2+ exchange in the generation of superoxide radicals by human neutrophils. J Biol Chem (265): 13449-56, 1990. [Full Text/Abstract]

Simchowitz L Bibb JA Functional analysis of the modes of anion transport in neutrophils and HL-60 cells. Annu Rev Physiol (52): 381-97, 1990. [Full Text/Abstract]

Simchowitz L Davis AO Intracellular pH recovery from alkalinization. Characterization of chloride and bicarbonate transport by the anion exchange system of human neutrophils. J Gen Physiol (96): 1037-59, 1990. [Full Text/Abstract]

Simchowitz L Jacobson E Management of hyperuricemia Modern Med(58): 72-84, 1990.

Simchowitz L Cragoe EJ Jr Polyvalent cations inhibit human neutrophil chemotaxis by interfering with the polymerization of actin. J Biol Chem (265): 13457-63, 1990. [Full Text/Abstract]

Foy MA Simchowitz L Recent developments in leukocyte research. Year Immunol (4): 208-17, 1989. [Full Text/Abstract]

Simchowitz L Davis AO Sulfate transport in human neutrophils. J Gen Physiol (94): 95-124, 1989. [Full Text/Abstract]

Simchowitz L Interactions of bromide, iodide, and fluoride with the pathways of chloride transport and diffusion in human neutrophils. J Gen Physiol (91): 835-60, 1988. [Full Text/Abstract]

Simchowitz L Lithium movements in resting and chemotactic factor-activated human neutrophils. Am J Physiol (254): C526-34, 1988. [Full Text/Abstract]

Simchowitz L Cragoe EJ Jr Na+-Ca2+ exchange in human neutrophils. Am J Physiol (254): C150-64, 1988. [Full Text/Abstract]

Simchowitz L Properties of the principal anion-exchange mechanism in human neutrophils. Soc Gen Physiol Ser (43): 193-208, 1988. [Full Text/Abstract]

Simchowitz L Receptor modulation and cell activation: a journey of a thousand miles begins with one step. J Lab Clin Med (111): 361-2, 1988. [Full Text/Abstract]

Simchowitz L Woltersdorf OW Jr Cragoe EJ Jr Intracellular accumulation of potent amiloride analogues by human neutrophils. J Biol Chem (262): 15875-85, 1987. [Full Text/Abstract]

Simchowitz L Cragoe EJ Jr Intracellular acidification-induced alkali metal cation/H+ exchange in human neutrophils. J Gen Physiol (90): 737-62, 1987. [Full Text/Abstract]

Simchowitz L Ratzlaff R De Weer P Anion/anion exchange in human neutrophils. J Gen Physiol (88): 195-217, 1986. [Full Text/Abstract]

Simchowitz L De Weer P Chloride movements in human neutrophils. Diffusion, exchange, and active transport. J Gen Physiol (88): 167-94, 1986. [Full Text/Abstract]

Simchowitz L Cragoe EJ Jr Inhibition of chemotactic factor-activated Na+/H+ exchange in human neutrophils by analogues of amiloride: structure-activity relationships in the amiloride series. Mol Pharmacol (30): 112-20, 1986. [Full Text/Abstract]

Simchowitz L Cragoe EJ Jr Regulation of human neutrophil chemotaxis by intracellular pH. J Biol Chem (261): 6492-500, 1986. [Full Text/Abstract]

Simchowitz L Chemotactic factor-induced activation of Na+/H+ exchange in human neutrophils. I. Sodium fluxes. J Biol Chem (260): 13237-47, 1985. [Full Text/Abstract]

Simchowitz L Chemotactic factor-induced activation of Na+/H+ exchange in human neutrophils. II. Intracellular pH changes. J Biol Chem (260): 13248-55, 1985. [Full Text/Abstract]

Simchowitz L Current trends in leukocyte activation. Year Immunol : 122-8, 1985. [Full Text/Abstract]

Simchowitz L Intracellular pH modulates the generation of superoxide radicals by human neutrophils. J Clin Invest (76): 1079-89, 1985. [Full Text/Abstract]

Simchowitz L Roos A Regulation of intracellular pH in human neutrophils. J Gen Physiol (85): 443-70, 1985. [Full Text/Abstract]

Simchowitz L Biochemical events in cell activation. Surv Immunol Res (3): 286-7, 1984. [Full Text/Abstract]

Simchowitz L Phagocytic cell function--an overview of recent advances. Surv Immunol Res (3): 150-3, 1984. [Full Text/Abstract]

Spilberg I Mehta J Muniain MA Simchowitz L Atkinson J Receptor blockade as a mechanism of deactivation of human neutrophils by pepstatin and formyl-Met-Leu-Phe. Inflammation (8): 73-86, 1984. [Full Text/Abstract]

Simchowitz L Spilberg I Atkinson JP Evidence that the functional responses of human neutrophils occur independently of transient elevations in cyclic AMP levels. J Cyclic Nucleotide Protein Phosphor Res (9): 35-47, 1983. [Full Text/Abstract]

Simchowitz L Phagocytic cell function. An overview of recent advances. Surv Immunol Res (2): 255-7, 1983. [Full Text/Abstract]

Atkinson JP Simchowitz L Mehta J Stenson WF 5,8,11,14-Eicosatetraynoic acid (ETYA) inhibits binding of N-formyl-methionyl-leucyl-phenylalanine (FLMP) to its receptor on human granulocytes. A note of caution. Immunopharmacology (4): 1-9, 1982. [Full Text/Abstract]

Spilberg I Mehta J Simchowitz L Induction of a chemotactic factor from human neutrophils by diverse crystals. J Lab Clin Med (100): 399-404, 1982. [Full Text/Abstract]

Simchowitz L Spilberg I De Weer P Sodium and potassium fluxes and membrane potential of human neutrophils: evidence for an electrogenic sodium pump. J Gen Physiol (79): 453-79, 1982. [Full Text/Abstract]

Simchowitz L Atkinson JP Spilberg I Stimulation of the respiratory burst in human neutrophils by crystal phagocytosis. Arthritis Rheum (25): 181-8, 1982. [Full Text/Abstract]

Spilberg I Mehta J Daughaday C Simchowitz L Determination of a specific receptor for formyl-methionyl-leucyl-phenylalanine on th pulmonary alveolar macrophage and its relationship to chemotaxis and superoxide production. J Lab Clin Med(97): 602-9, 1981. [Full Text/Abstract]

Wedner HJ Simchowitz L Stenson WF Fischman CM Inhibition of human polymorphonuclear leukocyte function by 2-cyclohexene-1-one. A role for glutathione in cell activation. J Clin Invest(68): 535-43, 1981. [Full Text/Abstract]

Spilberg I McLain D Simchowitz L Berney S Colchicine and pseudogout. Arthritis Rheum(23): 1062-3, 1980. [Full Text/Abstract]

Simchowitz L Fischbein LC Spilberg I Atkinson JP Induction of a transient elevation in intracellular levels of adenosine-3'',5''-cyclic monophosphate by chemotactic factors: an early event in human neutrophil activation. J Immunol(124): 1482-91, 1980. [Full Text/Abstract]

Simchowitz L Atkinson JP Spilberg I Stimulus-specific deactivation of chemotactic factor-induced cyclic AMP response and superoxide generation by human neutrophils. J Clin Invest(66): 736-47, 1980. [Full Text/Abstract]

Simchowitz L Spilberg I Atkinson JP Superoxide generation and granule enzyme release induced by ionophore A23187. Studies on the early events of neutrophil activation. J Lab Clin Med(96): 408-24, 1980. [Full Text/Abstract]

Simchowitz L Mehta J Spilberg I Chemotactic factor-induced generation of superoxide radicals by human neutrophils: effect of metabolic inhibitors and antiinflammatory drugs. Arthritis Rheum(22): 755-63, 1979. [Full Text/Abstract]

Simchowitz L Spilberg I Chemotactic factor-induced generation of superoxide radicals by human neutrophils: evidence for the role of sodium. J Immunol(123): 2428-35, 1979. [Full Text/Abstract]

Simchowitz L Mehta J Spilberg I Chemotactic factor-induced superoxide radical generation by human neutrophils: requirement for proteinase (esterase) activity. J Lab Clin Med(94): 403-13, 1979. [Full Text/Abstract]

Simchowitz L Spilberg I Evidence for the role of superoxide radicals in neutrophil-mediated cytotoxicity. Immunology(37): 301-9, 1979. [Full Text/Abstract]

Simchowitz L Spilberg I Generation of superoxide radicals by human peripheral neutrophils activated by chemotactic factor. Evidence for the role of calcium. J Lab Clin Med(93): 583-93, 1979. [Full Text/Abstract]

Spilberg I Mandell B Mehta J Simchowitz L Rosenberg D Mechanism of action of colchicine in acute urate crystal-induced arthritis. J Clin Invest(64): 775-80, 1979. [Full Text/Abstract]

Spilberg I Mandell B Mehta J Sullivan T Simchowitz L Dissociation of the neutrophill functions of exocytosis and chemotaxis. J Lab Clin Med(92): 297-302, 1978. [Full Text/Abstract]

Simchowitz L Schur PH Antibody-dependent lymphocyte-mediated cytotoxicity. The nature of the effector cell and characterization of its fc receptor. Scand J Immunol(5): 759-69, 1976. [Full Text/Abstract]

Stillman JS Barry PE Bell CL Gibson DJ Glass DM Lewis RA Medof ME Simchowitz L Clinical characteristics and classification of juvenile rheumatoid arthritis. In: Still's Disease: Juvenile Chronic Polyarthritis. Jayson MIV, editors. Academic Press, 1976. pp.47-58

Simchowitz L Schur PH Lectin-dependent neutrophil-mediated cytotoxicity. I. Characteristics. Immunology (31): 303-11, 1976. [Full Text/Abstract]

Simchowitz L Schur PH Lectin-dependent neutrophil-mediated cytotoxicity. II. Possible mechanisms. Immunology(31): 313-22, 1976. [Full Text/Abstract]


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