Mutations in a single gene, the cystic fibrosis transmembrane conductance regulator (CFTR), are responsible for this disease. 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). A., Daddona, P., Gardner, P., Huang, M. T. Efficient and persistent gene transfer of AAV-CFTR in maxillary sinus. View details for Web of Science ID A1993KH62000095. In the Ashkenazi Jewish population, serious and lethal genetic conditions occur with relatively high frequency. Schrijver, I., Ramalingam, S., Sankaran, R., Swanson, S., Dunlop, C. L., Keiles, S., Moss, R. B., Oehlert, J., Gardner, P., Wassman, E. R., Kammesheidt, A. 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. Phyllis Gardner knew from the moment the 19-year-old student started talking about her "brilliant" idea that it wouldn't work. The Stanford professor was one of the first people to doubt Holmes' credentials and products, dismissing Holmes' patch idea when she was a 19-year-old student at the university. Because GSK-3 responds to signals initiated by Wnt and other ligands, NF-AT family members could be effectors of these pathways. 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. MED 299: Directed Reading in Medicine (Autumn, Winter, Spring, Summer) MED 280: Early Clinical Experience in Medicine (Autumn, Winter, Spring, Summer) The Sunday Times' tech correspondent brings on Dr Phyllis Gardner, the Standord medical professor who came across Elizabeth Holmes before she started Theranos and then worked behind the scenes to expose her, to talk about her background at Stanford (4:00), and in industry (5:00), meeting a young Elizabeth Holmes (6:55), rejecting her first idea 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. 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. View details for Web of Science ID A1992KF37500001. View details for Web of Science ID 000231054600008. In particular, the steady-state rise in interleukin-2 (T-cell growth factor) mRNA is dependent on the rise of [Ca2+]i resulting from ion movement across this channel. Specific attenuation of interleukin-2 transcriptional induction occurs in Jurkat T cells following pretreatment with a Ca2+ ionophore. By means of arrayed primer extension technology, we have designed a genotyping microarray with 204 probe sites for CF transmembrane conductance regulator gene mutation detection. Support Lucile Packard Children's Hospital Stanford and child and maternal health. 3. It is unclear whether or not this type of Ca2+ channel is present in straight B-cell lines. 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. Homozygous and compound heterozygous pathogenic mutations were exclusively seen in affected individuals. (ABSTRACT TRUNCATED AT 400 WORDS), View details for Web of Science ID A1990DA09800009. Support teaching, research, and patient care. Rodriguez-Paris, J., Ballay, C., Inserra, M., Stidham, K., Colen, T., Roberson, J., Gardner, P., Schrijver, I. 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. 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. Maldonado, D., Schumann, M., Nghiem, P., Dong, Y., Gardner, P. REGULATION OF CL- CHANNELS BY MULTIFUNCTIONAL CAM KINASE. Clinical manifestations include both pancreatic and pulmonary insufficiency. 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. The involvement of CFTR suggests a possible cystic fibrosis heterozygote advantage against STa-induced diarrhea. View details for Web of Science ID A1996VQ33800028, View details for PubMedCentralID PMC2200601. She has served on the board of directors of several public and private companies, including . The role of calcium in the action of tumor necrosis factor (TNF) on human neutrophils is not clear. Nishimoto, I., Wagner, J. We realize that a Troy High School year book may be hard to . 4. Register to let other graduates of Troy High School find and contact you. A., Schulman, H., Gardner, P. ACTIVATION OF CHLORIDE CHANNELS IN NORMAL AND CYSTIC-FIBROSIS AIRWAY EPITHELIAL-CELLS BY MULTIFUNCTIONAL CALCIUM CALMODULIN-DEPENDENT PROTEIN-KINASE. A significant proportion (78/85) of the different mutations identified would not have been detected by the ACMG/ACOG-recommended 25-mutation screening panel. In T-cells, a number of important kinases, phosphatases, and cytoskeleton-modulating enzymes are functionally Ca dependent but have no Ca-binding domains and therefore must sense changes in the cytoplasmic Ca level through interactions with Ca-binding proteins. This leads to production of inositol 1,4,5-trisphosphate, release of stored intracellular Ca, and activation of Ca-permeable plasma membrane channels. In this review, we discuss agents that increase Cl- secretion via preserved Cl- secretory pathways, such as uridine triphosphate, or that enhance Na+ resorption, such as amiloride, thereby correcting altered airway secretions. She is currently a tenured professor at the School of Medicine at Stanford University . Significant transduction of the tissue was observed and histochemical staining was used to identify enterocytes as the primary targets of gene transfer. When tested, persistence was observed in one patient for 41 days and in another for 10 weeks. Exclusion criteria comprised known causes of hearing loss such as significant noise exposure, trauma, ototoxic medication, neoplasm, and congenital infection or syndrome, as well as congenital or pediatric onset. Phyllis Gardner (Professor) Manage my profile (650) 387-9319 pgardner. She trained in Internal Medicine at Massachusetts General Hospital, followed by a Chief Residency at Stanford University Hospital. Leflunomide, a novel immunosuppressive drug, prolongs experimental graft survival effectively and has been well tolerated in patients with rheumatoid arthritis. However, newer therapies directed at the specific underlying defects have emerged. Raising intracellular free calcium concentration from 2 to 200 nM reversed the reduction, induced by substance P, in current peak amplitude and disclosed an apparent desensitization towards the neuropeptide action. Premack, B. There is also an associated K+ efflux and membrane hyperpolarization. Sustained elevation of intracellular Ca2+ by cell surface receptors is often dependent on influx of Ca2+ across the plasma membrane through routes not involving voltage-gated Ca2+ channels. Phyllis Gardner Age: 68 Position: Professor of medicine at Stanford, board member at Revance Therapeutics and CohBar. Phyllis Gardner Professor of Medicine (Clinical Pharmacology) Medicine - Clinical Pharmacology Bio ACADEMIC APPOINTMENTS Professor, Medicine - Clinical Pharmacology Research & Scholarship CURRENT RESEARCH AND SCHOLARLY INTERESTS IL-8 concentration rose in sinus fluids from affected sinuses. Hence, the cAMP and calcium pathways are separate. Furthermore, currents flowing through Ca2+-permeable channels are apparently autoregulated, as inward conductance is abolished by elevation of Ca2+ concentration in the bathing solution. Beals, C. R., Sheridan, C. M., Turck, C. W., Gardner, P., Crabtree, G. R. Reduced IL-10 secretion by CD4(+) T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR). View details for Web of Science ID A1992HD15400067. 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. Although great strides have been made in the treatment of CF, it remains lethal, often by early adulthood. It has been suggested that P-glycoprotein (P-gp), an ATP-dependent transporter responsible for classical multidrug resistance, is also a volume-regulated chloride channel. The site facilitates research and collaboration in academic endeavors. 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. Contact. This action was blocked by substituting Cs+ for K+ in the recording pipette and by the substance P antagonist. Dr. Phyllis Gardner, MD, is an Internal Medicine specialist practicing in Stanford, CA with 47 years of experience. 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. Stanford professor Phyllis Gardner, MD, has been an outspoken skeptic of Elizabeth Holmes, and her now defunct company Theranos for years. 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. By means of path clamp recording and associated cell and molecular biological techniques, we have studied:1. The mechanism of TCR-stimulated Ca2+ influx was studied in the Jurkat human T cell line using Ca2+ indicator dyes and whole-cell patch clamp. About Phyllis Gardner, M.D. 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. The half-life of functional CFTR is less than 24 h in these cells. She is survived by daughters Gina & Michelle as well as seven grandchildren, six great-grandchildren, and her last remaining sibling, Larry. Phyllis I. Gardner (born July 7, 1950) is a Professor of Medicine at the Stanford University School of Medicine. CFTR involvement in cAMP regulation of Cl- conductance in lymphocytes is further supported by our demonstration of the presence of appropriately spliced CFTR mRNA segments in human B and T lymphocytes as detected by an optimized reverse-transcription and polymerase chain reaction approach. These results are consistent with the activation of Cl- secretion via a P1 purinoceptor. 5. 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.. 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. Foreman, P. K., Wainwright, M. J., Alicke, B., Kovesdi, I., Wickham, T. J., Smith, J. G., Meier-Davis, S., Fix, J. We find that intracellular application of activated kinase and ATP activates a Cl- current similar to that activated by a Ca2+ ionophore, that peptide inhibitors of either the kinase or calmodulin block Ca2(+)-dependent activation of Cl- channels, and that a peptide inhibitor of protein kinase C does not block Ca2(+)-dependent activation. View details for Web of Science ID A1994NA28800008, View details for Web of Science ID A1994BB86U00010. The channel appeared to be identical to the previously described voltage-insensitive, messenger-mediated, calcium-permeable channel involved in T cell activation. A77 1726, the active metabolite of leflunomide, inhibits lymphocyte proliferation in vitro. View details for Web of Science ID 000083463500002. DBHQ stimulated 125I efflux and mobilized intracellular free Ca2+ in a dose-dependent manner. The page you requested cannot be found. She graduated from Harvard University / School Of Medicine in 1976. With fluorescent cytometry, using the visible wavelength calcium probe, fluo-3, and patch clamping, we investigated whether TNF induces cytosolic free Ca2+ changes and Ca(2+)-activated Cl- current, respectively. In this study we used 125I efflux and whole-cell patch-clamp studies to investigate whether prostaglandin E1 (PGE1), an agonist that generates intracellular cAMP in Jurkat T lymphocytes, activates a Cl- conductance. T cell clones (TCC) from controls and CF patients displayed equivalent Ca(2+)-mediated Cl- current; however, TCC from patients with CF but not controls displayed defective cAMP-mediated Cl-current. The identity of the amplified products was confirmed by hybridization to CFTR-specific probes and DNA sequencing. Addition of adenosine (ADO; 0.1-1 mM) markedly increased 125I efflux rate. Schrijver, I., Kulm, M., Gardner, P. I., Pergament, E. P., Fiddler, M. B. Holmes forged ahead anyway. 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. Cystic fibrosis (CF), a lethal disease common to Caucasians, is characterized by a defect in the CF transmembrane conductance regulator and the resulting defective cAMP-regulated Cl- secretion by epithelial cells. About Phyllis Gardner, M.D. However, chronic respiratory inflammation and infection remain unexplained phenomena in disease pathogenesis. 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. The predominant effect of Bay K 8644 on these channels was to increase the probability of channel reopening, apparently without a major effect on mean channel open-time. View details for Web of Science ID A1989AX58900003. Dr. Gardner is currently a Professor with tenure at the School of Medicine at Stanford University, where she has held several positions since she began there in 1984, including Senior Associate Dean for Education and Student Affairs. A group of 257 self-identified Hispanics with clinical manifestations consistent with CF were studied by temporal temperature gradient electrophoresis and/or DNA sequencing. In contrast, the calcium-activated chloride current was not affected by antisense treatment. For each patient, a dose of 100,000 replication units of tgAAVCF was administered to one maxillary sinus, while the contralateral maxillary sinus received a placebo treatment, thereby establishing an inpatient control. Traditional therapeutic modalities address these problems with pancreatic enzyme replacement, vitamins and nutritional supplementation, antibiotics, and respiratory therapy. 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. Professor of Medicine (Clinical Pharmacology) Medicine - Med/Clinical Pharmacology University - Faculty 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. These findings not only delineate a novel transduction mechanism for nitric oxide but also support the hypothesis that an intrinsic immune defect may exist in cystic fibrosis. Dose-dependent changes in TEPD responses to pharmacologic intervention were observed following treatments. Assessing the biological activity and clinical efficacy of gene therapy is critically important in cystic fibrosis (CF). 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-. 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.

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