She worked within the hospitality management industry for well over 30 years. The identity of the amplified products was confirmed by hybridization to CFTR-specific probes and DNA sequencing. Stanford Hospital and Clinics. Hometown: Her father was a professor, so she grew up in college towns. Comprehensive arrayed primer extension array for the detection of 59 sequence variants in 15 conditions prevalent among the (Ashkenazi) Jewish population. When she told her professor Dr Phyllis Gardner about her idea, Gardner told her it was ambitious . Multifunctional CaM kinase also attenuated interleukin-2 activation by calcineurin plus phorbol ester. Using the Hereditary Hearing Loss arrayed primer extension (APEX) array, which contains 198 mutations across 8 hearing loss-associated genes (GJB2, GJB6, GJB3, GJA1, SLC26A4, SLC26A5, 12S-rRNA, and tRNA Ser), we compared the frequency of sequence variants in 94 individuals with early presbycusis to 50 unaffected controls and aimed to identify possible genetic contributors. These channels in normal cells are activated by cyclic AMP-dependent protein kinase and protein kinase C. In cystic fibrosis these kinases fail to activate otherwise normal Cl- channels. The effects of the dihydropyridine calcium channel agonist Bay K 8644 on indo-1-loaded Jurkat human leukemia T lymphocytes was assessed by flow cytometry. Multifunctional Ca2+/calmodulin-dependent protein kinase (CaM kinase) is a mediator of calcium signals in diverse signaling pathways. 5. T-cell receptor signalling activates multifunctional CaM kinase. Gardner, P., Oitmaa, E., Messner, A., Hoefsloot, L., Metspalu, A., Schrijver, I. Microfabricated nanochannel implantable drug delivery devices: trends, limitations and possibilities. We are interested in the general process of signal transduction, focusing on the role that ion channels play in this process. In summary, this Phase II trial confirms the safety of tgAAVCF but provides little support of its efficacy in the within-patient controlled sinus study. These results suggest that there is no relationship between P-gp and the chloride channel activated by cell swelling. 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. In addition, several other internal feedback controls on TCR/CD3 function, by CD4-induced tyrosine-specific phosphorylation of the CD3 zeta subunit, or on the Ca2+ signal, by extracellular Cl- or by GM1 gangliosides, are also postulated. In the Peyer's patches, a high level of expression was localized to epithelial cells, potentially M cells, overlying the lymphoid follicle domes. These results are consistent with the activation of Cl- secretion via a P1 purinoceptor. Characterization of CFTR mutations in the U.S. Hispanic population is vital to early diagnosis, genetic counseling, patient-specific treatment, and the understanding of cystic fibrosis (CF) pathogenesis. A defect in regulation of a chloride channel appears to be the molecular basis for cystic fibrosis (CF), a common lethal genetic disease. Site-directed mutagenesis of the predicted autoinhibitory domain yielded a mutant which was approximately 37% active in the absence of Ca2+/calmodulin, confirming the region as critical for autoregulation, and suggesting this mutant as a tool for studying the role of CaM kinase in nonneuronal tissues. About Dr. Phyllis Gardner. B., Messner, A. H., Moran, M. L., Batson, E. P., DiMiceli, S., Brown, B. W., Desch, J. K., Norbash, A. M., Conrad, C. K., Guggino, W. B., Flotte, T. R., Wine, J. J., Carter, B. J., Reynolds, T. C., Moss, R. B., Gardner, P. Safety and biological efficacy of an adeno-associated virus vector cystic fibrosis transmembrane regulator (AAV-CFTR) in the cystic fibrosis maxillary sinus. This difference was independent of atopy. View details for Web of Science ID 000177015400009. We show here that Ca2+ ionophore activates Cl- currents in cell-attached and whole-cell patch-clamp recordings of Jurkat T lymphocytes, but this activation is not direct. Traditional therapeutic modalities address these problems with pancreatic enzyme replacement, vitamins and nutritional supplementation, antibiotics, and respiratory therapy. It is unclear whether or not this type of Ca2+ channel is present in straight B-cell lines. Furthermore, currents flowing through Ca2+-permeable channels are apparently autoregulated, as inward conductance is abolished by elevation of Ca2+ concentration in the bathing solution. Phyllis Gardner, an American biologist, was born on July 7, 1950, and is well known for being one of the first to question and challenge Elizabeth Holmes' beliefs. A 48-h antisense treatment reduced the expression of CFTR protein as assayed by immunoprecipitation and autoradiography to 26% of the level in sense-treated T84 cells. This provider currently accepts 5 insurance plans. She is a Professor at Stanford University Medical Center. 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. 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. The effects of purinoceptor agonists on Cl- secretion were examined in a transformed cystic fibrosis airway phenotype epithelial cell line, CFPEo-. 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). Over one third of the mutations (27/85) occurred with a relative frequency >1%, which illustrates that the identified mutations are not all rare. We demonstrate here that volume-regulated chloride-selective currents can be induced in cells with or without P-gp expression. We conclude that CFTR mRNA is expressed in lymphocytes, consistent with the cAMP regulation of chloride transport present in normal lymphocytes but defective in CF-derived lymphocytes. Her research centered on cardiac arrhythmias, ion channel biophysiology, cell biology, cystic . Homozygous and compound heterozygous pathogenic mutations were exclusively seen in affected individuals. View details for Web of Science ID A1993KH62000095. The patients were between ages 20 and 65 yr, with adult-onset sensorineural hearing loss of unknown etiology, and carried a clinical diagnosis of early presbycusis. Dr. Gardner has spent more than 35 years in academia, medicine and industry. View details for Web of Science ID A1995RY95400014. These data provide evidence for a novel in vitro mechanism of the antiproliferative action of this immunosuppressant. Commercially available CF carrier screening panels offer a limited panel of mutations, however, making them insufficiently sensitive for certain groups within an ethnically diverse population. She took one to Dr. Phyllis Gardner, a Stanford Medical School professor. 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. An alternative to pulmonary testing of new CF treatments is use of the maxillary sinuses as a surrogate model of CF lung disease. 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. Expression of the CFTR protein is thought to be physiologically important only in exocrine epithelial cells. The channel appeared to be identical to the previously described voltage-insensitive, messenger-mediated, calcium-permeable channel involved in T cell activation. Dr. Phyllis Gardner, MD, is an Internal Medicine specialist practicing in Stanford, CA with 47 years of experience. View details for Web of Science ID A1994NM61500008. Here we show that STa, guanylin and cGMP each activate intestinal Cl- secretion, and that this is abolished by inhibitors of cAMP-dependent protein kinase (PKA), suggesting that PKA is a major mediator of this effect. Support Lucile Packard Children's Hospital Stanford and child and maternal health. These assays suggest a pore diameter in the order of 2 nm. 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. When transfected into Jurkat T cells, the gamma B cDNA encoded a functional kinase which cosedimented on sucrose gradients with endogenous T cell CaM kinase activity and formed a large multimeric enzyme. 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. 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. Gardner recently opened up about her distrust and dislike . A total of 183 mutations were identified, including 14 different amino acid-changing novel variants. MED 299: Directed Reading in Medicine (Autumn, Winter, Spring, Summer) MED 280: Early Clinical Experience in Medicine (Autumn, Winter, Spring, Summer) Amino acid differences between these isoforms and the rat brain gamma isoform (which we refer to as gamma A) are localized to the variable domain. Wagner, J. This is the first account of an organic inhibitor of the T cell Ca2+ current. Cystic fibrosis (CF), which is due to mutations in the cystic fibrosis transmembrane conductance regulator gene, is a common life-shortening disease. When external and internal Cl- were about equal, the current reversed at about zero mV, but when external Cl- was lowered from 157 to 7 mM the reversal potential shifted 75 mV in the positive direction, demonstrating that the current carrier was Cl-. Using CF sinusitis as a surrogate model for testing clinical efficacy of new treatments is attractive because CF upper respiratory disease is similar to the lower respiratory disease with respect to electrophysiology and microbiology.Sinusitis recurrence in untreated sinuses was analyzed during a prospective, randomized, unblinded, dose-escalation, within-subjects, phase I clinical trial of the adeno-associated virus mediated cystic fibrosis transmembrane conductance regulator (AAV-CFTR) gene transfer.Clinical symptoms combined with sinus endoscopy proved useful in the diagnosis of unilateral and bilateral sinusitis recurrence. IL-8 concentration rose in sinus fluids from affected sinuses. Gardner tried to. This pathway is defective in cystic fibrosis-derived human cloned T cells. View details for Web of Science ID A1988Q219900001, Department: Medicine - Med/Clinical Pharmacology, Genetic Analysis of Presbycusis by Arrayed Primer Extension. Dr. Phyllis I. Gardner is an internist in Stanford, California. Finally, a Ca2(+)-activated K+ channel in T cells has recently been described. These findings suggest that two Ca2+/calmodulin-responsive enzymes, multifunctional CaM kinase and calcineurin, could mediate the divergent effects of Ca2+ signals in T-lymphocyte regulation. New patients are welcome. The rank order of potency of purinoceptor agonists in stimulating 125I efflux was ADO > AMP > ADP approximately equal to ATP. Chao, A. C., ZIFFERBLATT, J. This channel presumably underlies the K+ efflux and membrane hyperpolarization that accompany the mitogen-induced increase in [Ca2+]i. Chao, A. C., deSauvage, F. J., Dong, Y. J., Wagner, J. The intestinal tract has many features that make it an attractive target for therapeutic gene transfer. Encina Hall West Suite 100 Stanford, CA 94305-6044 Phone: 650-723-1806 Campus Map Stimulation of T cells by externally applied PGE1 stimulated 125I efflux and activated a slowly developing membrane current. Specialties. . The host immune response and low vector efficiency have been key impediments to effective cystic fibrosis transmembrane regulator (CFTR) gene transfer for cystic fibrosis (CF). In the futuristic ideal, these systems would involve the implantation of precisely microfabricated drug delivery systems with nanopores, nanochannels and/or nanoreservoirs fabricated from silicon, coupled with electronic sensing and actuator systems, for the precise, timed and/or targeted delivery of drugs. In the present study, we investigated whether P1 agonist-induced Cl- secretion is preserved in cystic fibrosis airway epithelium and which signalling mechanism is involved. A prolonged (at least 2-4 hr) elevation of [Ca2+]i accompanies early T cell activation by TCR/CD3-specific ligands. We demonstrate that intracellular release of inositol 1,4,5-trisphosphate (InsP3), either from stimulation of transfected human muscarinic receptors or from photolytic release of caged InsP3, activates whole cell Ca2+ current in the Jurkat T cell line. First, patch clamp studies have revealed the presence of a nonvoltage-gated, Ca2+ permeable channel, the probability of whose opening increases upon exposure of the T cell to activating ligands. Clinical manifestations include both pancreatic and pulmonary insufficiency. We report here whole-cell patch clamp studies of normal and cystic fibrosis-derived airway epithelial cells showing that Cl- channel activation by Ca2+ is mediated by multifunctional Ca2+/calmodulin-dependent protein kinase. Nghiem, P., SAATI, S. M., Martens, C. L., Gardner, P., Schulman, H. FLASH-PHOTOLYSIS OF CAGED INOSITOL 1,4,5-TRISPHOSPHATE ACTIVATES PLASMA-MEMBRANE CALCIUM CURRENT IN HUMAN T-CELLS. This page may have moved, does not exist, or we may be experiencing a temporary issue. Lalonde, G., McDonald, T. V., Gardner, P., OHANLEY, P. D. A CAMP-REGULATED CHLORIDE CHANNEL IN LYMPHOCYTES THAT IS AFFECTED IN CYSTIC-FIBROSIS, TRIGGERING OF LYMPHOCYTES-T VIA EITHER T3-TI OR T11 SURFACE-STRUCTURES OPENS A VOLTAGE-INSENSITIVE PLASMA-MEMBRANE CALCIUM-PERMEABLE CHANNEL - REQUIREMENT FOR INTERLEUKIN-2 GENE-FUNCTION. Modulation of the voltage-gated K+ conductance in T-lymphocytes by substance P was examined. Phyllis Gardner knew from the moment the 19-year-old student started talking about her "brilliant" idea that it wouldn't work. The names listed below are alumni who have been searched for on this site from Troy High Schoolin Fullerton, California . View details for Web of Science ID 000078432500017. 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. She attended the Slade School of Fine Art and was a suffragette when they met. P1 purinoceptor agonists like adenosine have been shown to stimulate Cl- transport in secretory epithelia. The role of calcium in the action of tumor necrosis factor (TNF) on human neutrophils is not clear. Little or no inflammatory or immune responses were observed.AAV-CFTR administration to the maxillary sinus results in successful, dose-dependent gene transfer to the maxillary sinus and alterations in sinus TEPD suggestive of a functional effect, with little or no cytopathic or host immune response. Is CFTR also required for the calcium-dependent activation of chloride channels? Ca2+/calmodulin activation of Cl- channels presents a pathway with therapeutic potential for circumventing defective regulation of Cl- channels in cystic fibrosis. Further research promises to refine vector technology and bring CF gene therapy to the bedside. CFTR is required for the cAMP pathway but not for the calcium pathway. Phyllis Gardner Professor of Medicine (Clinical Pharmacology) Medicine - Clinical Pharmacology Bio ACADEMIC APPOINTMENTS Professor, Medicine - Clinical Pharmacology Research & Scholarship CURRENT RESEARCH AND SCHOLARLY INTERESTS DBHQ is a commercially available non-toxic synthetic compound chemically unrelated to THG and CPA. There is also an associated K+ efflux and membrane hyperpolarization. View details for Web of Science ID A1993KR82200022. Their conflicting politics, and his conflicted feelings, led the . Calcineurin dephosphorylates conserved serine residues in the amino terminus of NF-AT, resulting in nuclear import. A., Nepomuceno, I. Nishimoto, I., Wagner, J. It was 2002, and the student was a Stanford University sophomore. 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. Specific attenuation of interleukin-2 transcriptional induction occurs in Jurkat T cells following pretreatment with a Ca2+ ionophore. Premack, B. Previous work with excised inside-out patches suggests that inositol 1,4,5-trisphosphate is the activating second messenger of the voltage-insensitive T-cell Ca2+-permeable channel.
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