Professional Education


  • Doctor of Veterinary Medicine, University of Florida, Veterinary Medicine (2005)
  • Internship, Animal Medical Center, New York, Small Animal Medicine (2006)
  • Residency, Univ. of California, Davis, Companion Exotics (2009)
  • Dipl ABVP, American Board of Veterinary Practitioners, Avian Medicine (2009)

Current Research and Scholarly Interests


My current research focuses on novel methods to Erk1/2 MAP kinase (MAPK) cascade in cancer. Up-regulation occurs in >30% of human cancers, making this a key therapeutic target. MAPK scaffolds, such as IQGAP1, assemble pathway kinases together to effect signal transmission. Disrupting scaffold function offers a potentially orthogonal approach to MAPK cascade inhibition. We have IQGAP1 to be necessary for Ras-driven tumorigenesis and are utilizing this discovery to dissect the ERK1/2 pathway.

Lab Affiliations


Journal Articles


  • IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAP kinase-driven tumors. Nature medicine Jameson, K. L., Mazur, P. K., Zehnder, A. M., Zhang, J., Zarnegar, B., Sage, J., Khavari, P. A. 2013; 19 (5): 626-630

    Abstract

    Upregulation of the ERK1 and ERK2 (ERK1/2) MAP kinase (MAPK) cascade occurs in >30% of cancers, often through mutational activation of receptor tyrosine kinases or other upstream genes, including KRAS and BRAF. Efforts to target endogenous MAPKs are challenged by the fact that these kinases are required for viability in mammals. Additionally, the effectiveness of new inhibitors of mutant BRAF has been diminished by acquired tumor resistance through selection for BRAF-independent mechanisms of ERK1/2 induction. Furthermore, recently identified ERK1/2-inducing mutations in MEK1 and MEK2 (MEK1/2) MAPK genes in melanoma confer resistance to emerging therapeutic MEK inhibitors, underscoring the challenges facing direct kinase inhibition in cancer. MAPK scaffolds, such as IQ motif-containing GTPase activating protein 1 (IQGAP1), assemble pathway kinases to affect signal transmission, and disrupting scaffold function therefore offers an orthogonal approach to MAPK cascade inhibition. Consistent with this, we found a requirement for IQGAP1 in RAS-driven tumorigenesis in mouse and human tissue. In addition, the ERK1/2-binding IQGAP1 WW domain peptide disrupted IQGAP1-ERK1/2 interactions, inhibited RAS- and RAF-driven tumorigenesis, bypassed acquired resistance to the BRAF inhibitor vemurafenib (PLX-4032) and acted as a systemically deliverable therapeutic to significantly increase the lifespan of tumor-bearing mice. Scaffold-kinase interaction blockade acts by a mechanism distinct from direct kinase inhibition and may be a strategy to target overactive oncogenic kinase cascades in cancer.

    View details for DOI 10.1038/nm.3165

    View details for PubMedID 23603816

  • Control of somatic tissue differentiation by the long non-coding RNA TINCR NATURE Kretz, M., Siprashvili, Z., Chu, C., Webster, D. E., Zehnder, A., Qu, K., Lee, C. S., Flockhart, R. J., Groff, A. F., Chow, J., Johnston, D., Kim, G. E., Spitale, R. C., Flynn, R. A., Zheng, G. X., Aiyer, S., Raj, A., Rinn, J. L., Chang, H. Y., Khavari, P. A. 2013; 493 (7431): 231-U245

    Abstract

    Several of the thousands of human long non-coding RNAs (lncRNAs) have been functionally characterized; however, potential roles for lncRNAs in somatic tissue differentiation remain poorly understood. Here we show that a 3.7-kilobase lncRNA, terminal differentiation-induced ncRNA (TINCR), controls human epidermal differentiation by a post-transcriptional mechanism. TINCR is required for high messenger RNA abundance of key differentiation genes, many of which are mutated in human skin diseases, including FLG, LOR, ALOXE3, ALOX12B, ABCA12, CASP14 and ELOVL3. TINCR-deficient epidermis lacked terminal differentiation ultrastructure, including keratohyalin granules and intact lamellar bodies. Genome-scale RNA interactome analysis revealed that TINCR interacts with a range of differentiation mRNAs. TINCR-mRNA interaction occurs through a 25-nucleotide 'TINCR box' motif that is strongly enriched in interacting mRNAs and required for TINCR binding. A high-throughput screen to analyse TINCR binding capacity to approximately 9,400 human recombinant proteins revealed direct binding of TINCR RNA to the staufen1 (STAU1) protein. STAU1-deficient tissue recapitulated the impaired differentiation seen with TINCR depletion. Loss of UPF1 and UPF2, both of which are required for STAU1-mediated RNA decay, however, did not have differentiation effects. Instead, the TINCR-STAU1 complex seems to mediate stabilization of differentiation mRNAs, such as KRT80. These data identify TINCR as a key lncRNA required for somatic tissue differentiation, which occurs through lncRNA binding to differentiation mRNAs to ensure their expression.

    View details for DOI 10.1038/nature11661

    View details for Web of Science ID 000313259600041

    View details for PubMedID 23201690

  • Calculation of body surface area via computed tomography-guided modeling in domestic rabbits (Oryctolagus cuniculus) AMERICAN JOURNAL OF VETERINARY RESEARCH Zehnder, A. M., Hawkins, M. G., Trestrail, E. A., Holt, R. W., Kent, M. S. 2012; 73 (12): 1859-1863

    Abstract

    To optimize the use of CT-guided modeling for the calculation of body surface area (BSA) in domestic rabbits (Oryctolagus cuniculus). Animals-12 domestic rabbits.Adult rabbits (body weight, 1 to > 4 kg) that were client-owned animals undergoing CT for disease diagnosis or deceased laboratory animals donated from other research projects were scanned with a CT scanner. Images were transferred to a radiation therapy planning software program. Image slices were captured as contiguous slices at 100 kVp and 100 mA and processed to 0.1-cm-thick sections. The length of each contoured slice was summed to calculate a final BSA measurement. Nonlinear regression analysis was then used to derive an equation for the calculation of BSA in rabbits.The constant calculated by use of this method was 9.9 (range, 9.59 to 10). The R(2) for the goodness of fit was 0.9332. The equation that best described BSA as a function of body weight for domestic rabbits with this method was as follows: BSA = (9.9 × [body weight {in grams}](2/3))/10,000.The BSA calculated via the CT-guided method yielded results similar to those obtained with equations for other similarly sized mammals and verified the use of such equations for rabbits. Additionally, this technique can be used for species that lack equations for the accurate calculation of BSA.

    View details for Web of Science ID 000312513600001

    View details for PubMedID 23176410

  • Suppression of progenitor differentiation requires the long noncoding RNA ANCR GENES & DEVELOPMENT Kretz, M., Webster, D. E., Flockhart, R. J., Lee, C. S., Zehnder, A., Lopez-Pajares, V., Qu, K., Zheng, G. X., Chow, J., Kim, G. E., Rinn, J. L., Chang, H. Y., Siprashvili, Z., Khavari, P. A. 2012; 26 (4): 338-343

    Abstract

    Long noncoding RNAs (lncRNAs) regulate diverse processes, yet a potential role for lncRNAs in maintaining the undifferentiated state in somatic tissue progenitor cells remains uncharacterized. We used transcriptome sequencing and tiling arrays to compare lncRNA expression in epidermal progenitor populations versus differentiating cells. We identified ANCR (anti-differentiation ncRNA) as an 855-base-pair lncRNA down-regulated during differentiation. Depleting ANCR in progenitor-containing populations, without any other stimuli, led to rapid differentiation gene induction. In epidermis, ANCR loss abolished the normal exclusion of differentiation from the progenitor-containing compartment. The ANCR lncRNA is thus required to enforce the undifferentiated cell state within epidermis.

    View details for DOI 10.1101/gad.182121.111

    View details for Web of Science ID 000300626800004

    View details for PubMedID 22302877

  • Evaluation of indirect blood pressure monitoring in awake and anesthetized red-tailed hawks (Buteo jamaicensis): effects of cuff size, cuff placement, and monitoring equipment VETERINARY ANAESTHESIA AND ANALGESIA Zehnder, A. M., Hawkins, M. G., Pascoe, P. J., Kass, P. H. 2009; 36 (5): 464-479

    Abstract

    To compare Doppler and oscillometric methods of indirect arterial blood pressure (IBP) with direct arterial measurements in anesthetized and awake red-tailed hawks.Prospective, randomized, blinded study.Six, sex unknown, adult red-tailed hawks.Birds were anesthetized and IBP measurements were obtained by oscillometry (IBP-O) and Doppler (IBP-D) on the pectoral and pelvic limbs using three cuffs of different width based on limb circumference: cuff 1 (20-30% of circumference), cuff 2 (30-40%), and cuff 3 (40-50%). Direct arterial pressure measurements were obtained from the contralateral superficial ulnar artery. Indirect blood pressure measurements were compared to direct systolic arterial pressure (SAP) and mean arterial pressure (MAP) during normotension and induced states of hypotension and hypertension. Measurements were also obtained in awake, restrained birds. Three-way anova, linear regression and Bland-Altman analyses were used to evaluate the IBP-D data. Results are reported as mean bias (95% confidence intervals).The IBP-O monitor reported errors during 54% of the measurements. Indirect blood pressure Doppler measurements were most accurate with cuff 3 and were comparable to MAP with a bias of 2 (-9, 13 mmHg). However, this cuff consistently underestimated SAP with a bias of 33 (19, 48 mmHg). Variability in the readings within and among birds was high. There was no significant difference between sites of cuff placement. Awake birds had SAP, MAP and diastolic arterial pressure that were 56, 43, and 38 mmHg higher than anesthetized birds.Indirect blood pressure (oscillometric) measurements were unreliable in red-tailed hawks. Indirect blood pressure (Doppler) measurements were closer to MAP measurements than SAP measurements. There was slightly better agreement with the use of cuff 3 on either the pectoral or pelvic limbs. Awake, restrained birds have significantly higher arterial pressures than those under sevoflurane anesthesia.

    View details for DOI 10.1111/j.1467-2995.2009.00485.x

    View details for Web of Science ID 000269192300009

    View details for PubMedID 19709051

  • What is your diagnosis? Blood smear from an injured red-tailed hawk VETERINARY CLINICAL PATHOLOGY Johns, J. L., Luff, J. A., Shooshtari, M. P., Zehnder, A. M., Borjesson, D. L. 2009; 38 (2): 247-252

    Abstract

    An injured juvenile red-tailed hawk (Buteo jamaicensis) was evaluated at the Veterinary Medical Teaching Hospital at the University of California, Davis. The hawk was quiet, alert, and emaciated, and had a closed comminuted, mid-diaphyseal ulnar fracture. CBC results included heterophilia with a left shift, monocytosis, and increased plasma fibrinogen concentration. The blood smear included rare heterophils containing small, dark blue inclusions approximately 1-2 mum in diameter that ranged from round to coccobacillary in shape and formed variably shaped aggregates; the morphology of the inclusions was suspicious for Chlamydophila or Ehrlichia spp. pathogens. The hawk died, and histopathologic examination of tissues obtained at necropsy found severe multifocal histiocytic and heterophilic splenitis in addition to chronic hepatitis, myocarditis and epicarditis, meningoencephalitis, and airsacculitis. Using immunohistochemistry the presence of Chlamydia/Chlamydophila spp. antigen within multiple tissues was confirmed. Chlamydophila psittaci DNA was demonstrated in whole blood and fresh splenic tissue via real-time PCR. Direct fluorescent antibody staining of air-dried blood smears was positive in rare leukocytes for Chlamydia/Chlamydophila spp. antigen, and immunocytochemical staining of blood smears for Chlamydia/Chlamydophila spp. antigen was focally positive in rare heterophils. These findings may represent the first reported diagnosis of natural avian C. psittaci infection by visualization of organisms in peripheral blood heterophils. Immunocytochemical evaluation of blood smears was valuable in confirming the diagnosis and may be a useful antemortem test to discriminate between bacteria and other inclusions within heterophils.

    View details for DOI 10.1111/j.1939-165X.2008.00091.x

    View details for Web of Science ID 000266603300015

    View details for PubMedID 19228359

  • An unusual presentation of canine distemper virus infection in a domestic ferret (Mustela putorius furo) VETERINARY DERMATOLOGY Zehnder, A. M., Hawkins, M. G., Koski, M. A., Luff, J. A., Benak, J., Lowenstine, L. J., White, S. D. 2008; 19 (4): 232-238

    Abstract

    A 4.5-year-old, male castrated ferret was examined with a 27-day history of severe pruritus, generalized erythema and scaling. Skin scrapings and a trichogram were negative for mites and dermatophyte organisms. A fungal culture of hair samples was negative. The ferret was treated presumptively for scabies and secondary bacterial and yeast infection with selamectin, enrofloxacin, fluconazole, diphenhydramine and a miconazole-chlorhexidine shampoo. The ferret showed mild improvement in clinical signs over the subsequent 3 weeks, but was inappetent and required supportive feeding and subcutaneous fluids by the owner. The ferret was then examined on an emergency basis at the end of 3 weeks (53 days following initial signs of illness) for severe blood loss from a haematoma over the interscapular region, hypotension and shock. The owners elected euthanasia due to a poor prognosis and deteriorating condition. On post-mortem examination intraepithelial canine distemper viral inclusions were identified systemically, and abundant canine distemper virus antigen was identified with immunohistochemical staining. It is important to note the prolonged course of disease along with the absence of respiratory and neurological signs because this differs from the classic presentation of canine distemper virus infection in ferrets. Canine distemper virus should remain a clinical suspicion for ferrets with skin lesions that do not respond to appropriate therapy, even in animals that were previously vaccinated.

    View details for DOI 10.1111/j.1365-3164.2008.00677.x

    View details for Web of Science ID 000257699200008

    View details for PubMedID 18547381

  • Lacrimal cystadenoma in a Chinese box turtle (Cuora flavomarginata) JOURNAL OF ZOO AND WILDLIFE MEDICINE Kottwitz, J., Zehnder, A. M., Wyre, N., Aquino, S. 2008; 39 (1): 103-106

    Abstract

    An adult male Chinese box turtle (Cuora flavomarginata) presented to the Avian and Exotic Pet Service of the Animal Medical Center for periorbital swelling of the right eye. The swelling had failed to respond to nutritional supplementation and parenteral administration of vitamin A. What had initially presented as periorbital swelling developed into a growth ventral to the globe that impeded vision and was frequently traumatized by forelimb movements of the turtle. Twenty-six months after initial presentation, the turtle was anesthetized and the bulk of the mass was surgically removed. Histopathologic examination determined the mass to be a benign lacrimal cystadenoma.

    View details for Web of Science ID 000254006600014

    View details for PubMedID 18432103

  • The use of altrenogest to control aggression in a male Grant's Zebra (Equus burchelli boehmi) JOURNAL OF ZOO AND WILDLIFE MEDICINE Zelmder, A. M., Ramer, J. C., Proudfoot, J. S. 2006; 37 (1): 61-63

    Abstract

    A male Grant's Zebra (Equus burchelli boehmi) housed with two mares at the Indianapolis Zoo had a 9-yr history of intermittent aggressive behavior toward mares and other animals. Periods of separation allowed the mares time to heal after sustaining superficial bite wounds. On 26 March 2003, the male (890293) was started on altrenogest at a dosage of 19.8 mg orally once daily to allow reintroduction. The dosage was doubled (40 mg once a day) because of a perceived lack of response. Reintroduction to the mares occurred on 17 May 2003 with no signs of aggression noted. Treatment was reduced to 19.8 mg orally once a day and then discontinued. Altrenogest was restarted at 39.5 mg orally once a day because of the planned introduction of a new mare. There have been no major aggressive displays at this dosage of altrenogest and the dosage has recently been reduced following successful introduction of a new mare.

    View details for Web of Science ID 000237908600012

    View details for PubMedID 17312816