In addition, voltage-gated K+ channels, which closely resemble the delayed rectifier K+ channel of nerve and muscle, can be classified into three subtypes, according to their voltage dependence of activation, inactivation kinetics, and pharmacological sensitivity. Phyllis Gardner Professor of Medicine (Clinical Pharmacology) Medicine - Clinical Pharmacology Bio ACADEMIC APPOINTMENTS Professor, Medicine - Clinical Pharmacology Research & Scholarship CURRENT RESEARCH AND SCHOLARLY INTERESTS Ca2+ is generally thought to be an essential second messenger for early activation, but the precise molecular events contingent upon the Ca2+ signal remain to be determined. Gardner recently. In patch-clamp experiments, ADO (1 mM) induced an outwardly-rectified whole-cell Cl- current (baseline, 2.5 +/- 0.8 pA pF-1, + ADO, 78.4 +/- 23.8 pA pF-1; P < 0.02), which was largely inhibited in cells internally perfused with a selective inhibitory peptide of the multifunctional Ca2+/calmodulin-dependent protein kinase, CaMK [273-302] (20 microM), as compared to a control peptide, CaMK [284-302]. Pretreatment of CFPAC-1 cells with up to 50 microM DBHQ for 6 h did not cause any detectable change in cell viability and did not significantly affect the cell proliferation rate. She worked within the hospitality management industry for well over 30 years. We used RNase protection of this variable region to reveal the level of expression of gamma B and gamma C CaM kinase mRNAs in nine human tissues and cell lines. Phyllis I. Gardner, MD Director Dr. Phyllis Gardner has over 40 years of experience in academia, medicine and the healthcare industry. Stimulation of T-lymphocytes via either structure results in opening of an identical set of voltage-insensitive plasma membrane Ca2+-permeable channels through the action of a diffusible second messenger. Non-transformed, antigen-responsive CD4+ T cells cloned from healthy controls and CF patients homozygous or heterozygous for the delta F508 mutation transcribed CFTR mRNA and expressed immunoreactive cytoplasmic CFTR protein. 1. (1) A77 1726 dose-dependently inhibited the proliferation of Jurkat T cells (inhibitory concentration of 50% = 6 mumol/L); (2) A77 1726 did not decrease mobilization of intracellular Ca2+ stimulated by phytohemagglutinin or anti-CD3 monoclonal antibody; (3) A77 1726 did not inhibit interleukin-2 gene promoter activity in cells stimulated with ionomycin plus phorbol myristate acetate; (4) inhibition of cell proliferation by A77 1726 was antagonized by addition of uridine, cytidine, or 2(+)-deoxycytidine; (5) addition of uridine 24 hours after treatment with A77 1726 antagonized inhibition of proliferation; (6) A77 1726 was not antagonized by 2'-deoxyuridine, thymidine, adenosine, or guanosine. Over one third of the mutations (27/85) occurred with a relative frequency >1%, which illustrates that the identified mutations are not all rare. DBHQ is a commercially available non-toxic synthetic compound chemically unrelated to THG and CPA. Traditional therapeutic modalities address these problems with pancreatic enzyme replacement, vitamins and nutritional supplementation, antibiotics, and respiratory therapy. View details for Web of Science ID A1994PH77400001. Heat-stable enterotoxins (STa) produced by pathogenic bacteria induce profound salt and water secretion in the gut, leading to diarrhea. The arrayed primer extension genotyping microarray carries 59 sequence variant detection sites, of which 53 are detectable bi-directionally. We reexamined this hypothesis by use of whole-cell patch clamp recordings of three matched pairs of cell lines, which were either drug-sensitive or drug-resistant due to P-gp overexpression. STANFORD, CA - MAY 24: Stanford University professor Phyllis Gardner poses for a portrait on May 24, 2019, in Stanford, Calif. Gardner's blunt criticism of Theranos and its disgraced founder, Elizabeth Holmes, have made her a favorite among those who have closely followed the blood testing company's downfall. View details for DOI 10.1586/14737159.6.3.375, View details for Web of Science ID 000237916000010. Chao, A. C., Kouyama, K., Heist, E. K., Dong, Y. J., Gardner, P. ACTIVATION OF CFTR CHLORIDE CURRENT BY NITRIC-OXIDE IN HUMAN T-LYMPHOCYTES. A., Gardner, P. RECOMBINANT HUMAN TUMOR-NECROSIS-FACTOR-ALPHA INDUCES CALCIUM OSCILLATION AND CALCIUM-ACTIVATED CHLORIDE CURRENT IN HUMAN NEUTROPHILS - THE ROLE OF CALCIUM CALMODULIN-DEPENDENT PROTEIN-KINASE. One secondary endpoint, measurements of the anti-inflammatory cytokine IL-10 in sinus fluid, was significantly (p < 0.03) increased in the tgAAVCF-treated sinus relative to the placebo-treated sinus at day 90 after vector instillation. A luciferase assay quantitated interleukin-2 gene promoter activity in stimulated cells transfected with an interleukin-2 promoter-luciferase gene construct. In murine myeloma and hybridoma cells, a voltage-gated Ca2+ channel similar to Ca2+ channels in nerve, heart, and muscle is present. There have been major advances over the last several years in understanding the molecular basis of signaling by the T lymphocyte (T-cell) antigen receptor. A significant proportion (78/85) of the different mutations identified would not have been detected by the ACMG/ACOG-recommended 25-mutation screening panel. Single channel recordings by the extracellular patch-clamp technique indicated that Bay K 8644 activated an 8-pS, barium-permeable channel that opened as bursts of brief events. 6. Holmes wanted to build a patch that would scan the wearer for infections and release antibiotics. After surgically accessing the intestine, an E1-, E3-deleted adenoviral vector encoding beta-galactosidase (beta-Gal) was directly injected into various regions of the small and large intestine of rats and rabbits. DBHQ (25 microM) caused a short-term rise in [Ca2+]i in the absence of ambient Ca2+, and a sustained elevation of [Ca2+]i in cell monolayers bathed in the efflux solution (1.2 mM Ca2+), which was largely attenuated by Ni2+ (5 mM). A77 1726, the active metabolite of leflunomide, inhibits lymphocyte proliferation in vitro. Cao, W. W., Kao, P. N., Chao, A. C., Gardner, P., Ng, J., Morris, R. E. CALCIUM-DEPENDENT AND CAMKII-DEPENDENT CHLORIDE SECRETION INDUCED BY THE MICROSOMAL CA2+-ATPASE INHIBITOR 2,5-DI-(TERT-BUTYL)-1,4-HYDROQUINONE IN CYSTIC-FIBROSIS PANCREATIC EPITHELIAL-CELLS. CF is an early target for in vivo gene therapy, since it is a monogenic autosomal recessive disease in which restoration of normal cAMP-regulated Cl- conductance can be achieved by complementation with a normal gene. Addition of rhTNF alpha activated Cl- current in 80% of tested cells; the activated current was blocked by 10 microM 5-nitro-2-3-phenylpropylamino)benzoic acid, a Cl- channel blocker. This discrepancy is even more pronounced when such carrier screening panels are used for diagnostic purposes. The Stanford Medicine Alumni Association presents Women in Medicine and Science, Phyllis Gardner - Like a Salmon Swimming Upstream Stanford Medicine Alumni Awards 2022: Marian Carlson 3. Gardner, P., Oitmaa, E., Messner, A., Hoefsloot, L., Metspalu, A., Schrijver, I. Microfabricated nanochannel implantable drug delivery devices: trends, limitations and possibilities. Thus, DBHQ appears to enhance Cl- channel activity via a Ca(2+)-dependent mechanism involving CaMKII. Stimulation of human T-lymphocytes via either the surface T3-Ti antigen-major histocompatibility complex receptor complex or the T11 molecule results in clonal proliferation through a calcium-dependent mechanism. Hereditary sensorineural hearing loss: advances in molecular genetics and mutation analysis, Genotyping microarray for the detection of more than 200 CFTR mutations in ethnically diverse populations. The data demonstrate a modulation of T-lymphocyte K+ channels by substance P and substantiate a possible role for GTP-binding proteins in this modulation. Sinusitis recurred at a rate of 45% during one month of follow-up. Hearing loss has a genetic etiology in the majority of cases and is very common. View details for Web of Science ID A1989AU52300004. Although great strides have been made in the treatment of CF, it remains lethal, often by early adulthood. B-lymphoblasts from CF-affected humans demonstrated defective Cl- conductance regulation by cAMP but preserved regulation by calcium-mediated and volume regulation mechanisms. Michael Kovac // Getty Images Stanford professor Phyllis Gardner, MD, has been an outspoken skeptic of Elizabeth Holmes, and her now defunct company Theranos for years. Moss, R. B., BOCIAN, R. C., Hsu, Y. P., Dong, Y. J., Kemna, M., Wei, T., Gardner, P. Mechanism of the antiproliferative action of leflunomide - A77 1726, the active metabolite of leflunomide, does not block T-cell receptor-mediated signal transduction but its antiproliferative effects are antagonized by pyrimidine nucleosides. Stanford professor Phyllis Gardner, MD, has been an outspoken skeptic of Elizabeth Holmes, and her now defunct company Theranos for years. Voltage-insensitive Ca2+ channels, Ca2+-dependent K+ channels, other downstream Ca2+ dependent effector molecules; role in cellular activation and signal transduction.2. The half-life of functional CFTR is less than 24 h in these cells. This cost-effective array is based on a diversely applied platform technology and is suitable for both carrier screening and disease detection in Ashkenazi and Sephardic Jewish populations. A., Messner, A. H., Moran, M. L., DAIFUKU, R., Kouyama, K., Desch, J. K., Manley, S., Norbash, A. M., Conrad, C. K., Friborg, S., Reynolds, T., Guggino, W. B., Moss, R. B., Carter, B. J., Wine, J. J., Flotte, T. R., Gardner, P. Maxillary sinusitis as a surrogate model for CF gene therapy clinical trials in patients with antrostomies. Who Is Phyllis Gardner? Chao, A. C., ZIFFERBLATT, J. Phyllis Gardner. However, the absence of voltage-dependent activation, relative conductance sequence for divalent cations (Ca2+ > Ba2+ approximately Sr2+ > Mn2+), and lack of inhibition by nifedipine, D600, diltiazem, delta-conotoxin, or aga-IVa were unlike that of voltage-gated Ca2+ channels. Bath-application of DBHQ induced an outwardly-rectifying whole-cell Cl- current, which was abolished by pipette addition of BAPTA (5 mM) or CaMK [273-302] (20 microM), an inhibitory peptide of multifunctional Ca2+/calmodulin-dependent protein kinase (CaMKII). She sits on the Harvard Medical School Board of Fellows and the boards of biotechnology companies. Thus, lymphocytes may be an accessible source of CF tissue for study of this defect, for cloning of the chloride channel complex, and for diagnosis of the disease. Phyllis Gardner is part of Stanford Profiles, official site for faculty, postdocs, students and staff information (Expertise, Bio, Research, Publications, and more). 300 Pasteur Dr Stanford, CA 94305. SIGNAL TRANSDUCTION BY T-CELL RECEPTORS - MOBILIZATION OF CA AND REGULATION OF CA-DEPENDENT EFFECTOR MOLECULES, ANTISENSE OLIGODEOXYNUCLEOTIDES TO THE CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR INHIBIT CAMP-ACTIVATED BUT NOT CALCIUM-ACTIVATED CHLORIDE CURRENTS. Dr. Gardner has spent more than 35 years in academia, medicine and industry. Wagner, J. View details for Web of Science ID A1991GP26900012. View details for Web of Science ID 000228736900018. tgAAVCF, an adeno-associated cystic fibrosis transmembrane conductance regulator (CFTR) viral vector/gene construct, was administered to 23 patients in a Phase II, double-blind, randomized, placebo-controlled clinical trial. Their conflicting politics, and his conflicted feelings, led the . The initial technical evaluation of this microarray demonstrates that it is comprehensive, robust, sensitive, specific, and easily modifiable. Secretion of interferon-gamma, IL-2, and IL-4 was comparable in CF and control TCC after both forms of activation, while IL-5 was reduced in CF TCC following anti-CD3/phorbol myristate acetate (PMA) but not after Con A. Cystic fibrosis is associated with defective regulation of apical membrane chloride channels in airway epithelial cells. Phyllis Gardner was a skeptic of Elizabeth Holmes dating back to when she met Holmes, nearly 20 years ago. Gardner and. P1 purinoceptor agonists like adenosine have been shown to stimulate Cl- transport in secretory epithelia. View details for Web of Science ID A1993KH62000095. The ability of SK&F 96365 to inhibit IL-2 synthesis and cell proliferation suggests that a new class of related Ca2+ channel blockers can be developed as immunosuppressive agents. An adeno-associated virus vector (AAV-CFTR) was used in a phase I dose-escalation study to transfer CFTR cDNA into respiratory epithelial cells of the maxillary sinus of 10 CF patients.A prospective, randomized, unblinded, dose-escalation, within-subjects, phase I clinical trial of AAV-CFTR was conducted.Ten patients with previous bilateral maxillary antrostomies were treated.Safety, gene transfer as measured by semiquantitative polymerase chain reaction (PCR), and sinus transepithelial potential difference (TEPD) were measured.The highest level of gene transfer was observed in the range of 0.1-1 AAV-CFTR vector copy per cell in biopsy specimens obtained 2 weeks after treatment. Although CF-derived TCC preserved mitogen and antigen proliferative responses and specificity to tetanus toxoid epitopes, they selectively secreted approximately 45% less IL-10 compared with control TCC after activation with concanavalin A (Con A) (624 +/- 101 versus 1564 +/- 401 pg/ml per 10(6) cells, respectively; P = 0.04) or anti-CD3/phorbol ester (5148 +/- 1634 versus 11788 +/- 2390 pg/ml; P = 0.05). She has served on the board of directors of several public and private companies, including . A., McDonald, T. V., NGHIEM, P. T., Lowe, A. W., Schulman, H., Gruenert, D. C., Stryer, L., Gardner, P. HUMAN-LYMPHOCYTES TRANSCRIBE THE CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR GENE AND EXHIBIT CF-DEFECTIVE CAMP-REGULATED CHLORIDE CURRENT. It is possible that disruption of IL-10-mediated anti-inflammatory homeostasis may contribute to early onset sustained inflammation in CF airways. The names listed below are alumni who have been searched for on this site from Troy High Schoolin Fullerton, California . To study the mechanism by which rhTNF alpha induced Ca(2+)-activated Cl- current, we examined the involvement of calcium/calmodulin-dependent protein kinase (CaM kinase). Purification of the NF-AT kinase revealed that it is composed of a priming kinase activity and glycogen synthase kinase-3 (GSK-3). Sense and misantisense oligomers served as controls. Register to let other graduates of Troy High School find and contact you. Dong, Y. J., Chao, A. C., Kouyama, K., Hsu, Y. P., BOCIAN, R. C., Moss, R. B., Gardner, P. MOLECULAR STRATEGIES FOR THERAPY OF CYSTIC-FIBROSIS, INHIBITION BY SK-AND-F-96365 OF CA2+ CURRENT, IL-2 PRODUCTION AND ACTIVATION IN T-LYMPHOCYTES. 5. Support teaching, research, and patient care. The P1 agonists tested (at 0.01 and 0.1 mM) revealed a rank order of potency of 5'-N-ethylcarboxamine adenosine (NECA) > 2-chloro-adenosine (2-Cl-ADO) > R-phenylisopropyl adenosine (R-PIA). Phyllis Gardner (6 October 1890 - 16 February 1939) was a writer, artist, and noted breeder of Irish Wolfhounds. Since there is a significant increase in phosphoinositide turnover after stimulation via either the T3-Ti or T11 pathway, it is suggested that triggering of either structure opens a common set of channels through this mechanism. 61 comments She's a professor of medicine at Stanford and a former partner in a health care venture capital firm. Mutations in a single gene, the cystic fibrosis transmembrane conductance regulator (CFTR), are responsible for this disease. Whole-cell patch clamp revealed that a 48-h antisense treatment of T84 and 56FHTE-8o- fetal tracheal epithelial cells reduced the cAMP-activated chloride current to approximately 10% of that in sense-treated cells. She graduated from Harvard University / School Of Medicine in 1976. One of the best moments happens early in the series during a heated exchange between then-Stanford student Holmes and Stanford professor of medicine Phyllis Gardner (Laurie Metcalf,. It seems likely that rapid progress will be made in our understanding of these areas through a combination of immunological, biochemical, and electrophysiological approaches. cAMP kinase has been shown to mediate the cAMP pathway for regulation of Cl- channels in lymphocytes, but the mediator of an alternative, Ca2+ pathway has not been identified. Bacterial cultures and increased sinus leukocytes corroborated recurrent sinusitis. The results suggest that the dihydropyridine Ca agonist Bay K 8644 interacts with both voltage-gated and receptor-operated Ca channels and also suggest potential strategies for development of a new class of immunomodulatory drugs. Furthermore, the 3'-end of the gene was found in a T cell cDNA library. Phase I/II AAV-CFTR gene therapy trials.3. View details for Web of Science ID A1989AX58900003. Dr. Phyllis Gardner Despite Holmes' ability to charm older white businessman, assembling an impressive all-male board of directors at Theranos, there was one person who told her what she was. McDonald, T. V., NGHIEM, P. T., Gardner, P., Martens, C. L. PROSTAGLANDIN-E1 ACTIVATES A CHLORIDE CURRENT IN JURKAT-T LYMPHOCYTES VIA CAMP-DEPENDENT PROTEIN-KINASE. The linear relationship of current amplitude to holding potential when examined over the -60 to +60 mV range indicates that this pore has a constant mean single channel conductance level of 350-400 pS. Phyllis Gardner (Professor) Manage my profile (650) 387-9319 pgardner. Phospholipid bilayers composed of 1:1 w/w phosphotidylserine:phosphotidylethanolamine exposed to this toxin display discrete current flow events typical of transmembrane channels and consistent with the interpretation that this toxin acts by forming pores in phospholipid membranes. Ion channels, and ion fluxes in general, appear to regulate a wide variety of processes important to lymphocyte function in normal and disease states. Wagner, J. Several nonlinear internal feedback controls may contribute to the periodic nature of the Ca2+ signal: PKC-mediated phosphorylation of the CD3 gamma subunit, which is a feedback inhibitor of TCR/CD3 function; amplification of Ca2+ release from endoplasmic reticulum by a highly cooperative step in the opening of Ca2+ channels by InsP3, and Ca2+-dependent feedback enhancement of PLC function; autoregulatory negative feedback on Ca2+ influx by Ca2+, both by a direct effect on the plasma membrane Ca2+ channel and by induction of membrane hyperpolarization secondary to Ca2+-activated K+ efflux. Furthermore, Cl- channels are activated in excised patches by purified CaM kinase in a fashion that mimics the effect of Ca2+ ionophore in cell-attached recordings. However, newer therapies directed at the specific underlying defects have emerged. She took one to Dr. Phyllis Gardner, a Stanford Medical School professor. The effects of purinoceptor agonists on Cl- secretion were examined in a transformed cystic fibrosis airway phenotype epithelial cell line, CFPEo-. Intracellular administration of hydrolysis-resistant guanosine triphosphate (to persistently activate GTP-binding protein) and guanosine diphosphate (to competitively inhibit GTP-binding proteins) analogues mimicked and inhibited substance P-induced reduction of K+ conductance, respectively. Contact. (ABSTRACT TRUNCATED AT 400 WORDS), View details for Web of Science ID A1990DA09800009. She attended Stanford University, where she first came up with the idea for her company, Theranos. Lecturer in Management, Gradaute School of Business (2011 - Present) Lecturer, Department of Chemical Engineering (2009 - Present) Lecturer, Department of Chemical Engineering (2000 - 2003) Honors & Awards Fellow, American Institute of Medical and Biological Engineers (AIMBE) (2014 - Present) Member, National Academy of Engineering (2005 - Present) (1) A77 1726 inhibited Jurkat T-cell proliferation without inhibiting T-cell receptor-mediated signal transduction events, including tyrosine kinase-dependent intracellular Ca2+ mobilization and activation of the interleukin-2 gene promoter; (2) the antiproliferative effects of A77 1726 on Jurkat T cells are primarily due to interruption of de novo pyrimidine nucleotide biosynthesis. The identity of the amplified products was confirmed by hybridization to CFTR-specific probes and DNA sequencing. She has served on the board of directors of several public and private companies, including Revance Therapeutics, Corium International, Inc. and CohBar, Inc. Dr. Gardner has also served as an advisor to Change Health Care, Inc.. Lifetime resident of Fullerton, passed away on 11/18/21 in her home. A., Reynolds, T., Moran, M. L., Moss, R. B., Wine, J. J., Flotte, T. R., Gardner, P. A phase I/II study of tgAAV-CF for the treatment of chronic sinusitis in patients with cystic fibrosis. She received her medical degree from Harvard Medical School and has been in practice for more than 20 years. A group of 257 self-identified Hispanics with clinical manifestations consistent with CF were studied by temporal temperature gradient electrophoresis and/or DNA sequencing. A chloride ion transport defect has been described in human CF-derived lymphocytes; however, it has not been possible to detect CFTR mRNA in lymphocytes. View details for Web of Science ID A1994NM61500008. But Cl- flux in cystic fibrosis cells, as in normal cells, can be activated by raising intracellular Ca2+ (refs 5-10). Hence, the cAMP and calcium pathways are separate. While STa and guanylin bind to the same receptor guanylyl cyclase and raise cell cGMP, the signaling mechanism distal to cGMP remains controversial. Overexpression of either P-gp or cystic fibrosis transmembrane conductance regulator, the protein product of the CF gene and another member of the ATP-dependent transporters, is associated with a hypotonicity-induced, rapid onset, transient current prior to onset of the volume-sensitive chloride-selective current, an apparent nonspecific effect related to the overexpression of an integral membrane protein. Gardner tried to. Wagner, J. Cystic fibrosis C1-channels in epithelial cells and lymphocytes; associated signal transduction pathways and cell biological coupling mechanisms. View details for Web of Science ID A1993KR82200022. Phyllis Gardner (pictured), a professor of medicine at Stanford, criticized Elizabeth Holmes' blood testing company long before fraud charges were brought against her. A., COZENS, A. L., Schulman, H., Gruenert, D. C., Stryer, L., Gardner, P. PATCH CLAMP STUDIES OF LYMPHOCYTE-ACTIVATION, MODULATION OF MEMBRANE K+ CONDUCTANCE IN LYMPHOCYTES-T BY SUBSTANCE-P VIA A GTP-BINDING PROTEIN, IDENTIFICATION OF A HEMOLYSIN FROM ACTINOBACILLUS-PLEUROPNEUMONIAE AND CHARACTERIZATION OF ITS CHANNEL PROPERTIES IN PLANAR PHOSPHOLIPID-BILAYERS. Assessing the biological activity and clinical efficacy of gene therapy is critically important in cystic fibrosis (CF). Depletion of stored Ca2+ by either receptor stimulation or microsomal Ca(2+)-ATPase inhibition activated a low conductance, Ca(2+)-selective, non-voltage-activated membrane current. IL-8 concentration rose in sinus fluids from affected sinuses. This is the first account of an organic inhibitor of the T cell Ca2+ current.