Zachary Knight, PhD

TitleAssistant Professor
SchoolUCSF School of Medicine
Address1550 Fourth St
San Francisco CA 94158
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    Collapse Biography 
    Collapse Awards and Honors
    2016Helmholtz Young Investigator in Diabetes Award
    2016Pathway Award - American Diabetes Association
    2015NIH New Innovator Award
    2015Rita Allen Scholar Award
    2014Sloan Foundation Research Fellowship in Neuroscience
    2013Klingenstein Fellowship in Neurosciences
    2013NYSCF-Roberston Investigator Award
    2013McKnight Technological Innovations in Neuroscience Award
    2013NARSAD Young Investigator Award
    2009NIH Pathway to Independence Award
    2007Life Sciences Research Foundation Postdoctoral Fellowship
    2006UCSF Krevans Distinguished Dissertation Award
    2002Grand Prize Winner, National Collegiate Inventors Competition
    2001Howard Hughes Medical Institute Predoctoral Fellowship
    2000ARCS Foundation Predoctoral Fellowship

    Collapse Overview 
    Collapse Overview
    My laboratory studies the neurobiology of homeostasis in the mouse, including especially the mechanisms that control hunger, thirst, and body temperature. Our goal is to eludicate the structure and dynamics of the underlying neural circuits, so that we can begin to understand how these circuits give rise to motivated behaviors and further how they become dysregulated in conditions such as obesity. To address this challenge, we develop new technologies that enable the use of RNA sequencing to molecularly profile neurons that have specific activity patterns or connectivity. My lab has used these tools to discover new populations of neurons in the mouse brain that control feeding, drinking, and thermoregulation, and we are currently studying these cells and their associated circuits using a variety of modern approaches in neuroscience including mouse genetics, optogenetics, viral tracing, in vivo calcium imaging, and electrophysiology. Recently, my lab reported the discovery that AgRP and POMC neurons, two key cell types in the mouse brain that control hunger, are rapidly reset by sensory cues associated with food -- a finding that challenges longstanding assumptions about how the brain controls feeding. An ongoing interest of the lab is to understand how these and other homeostatic circuits integrate sensory information from the outside world with internal signals arising from the body in order to generate and shape goal-directed behaviors.

    Collapse Research 
    Collapse Research Activities and Funding
    Warm sensitive neurons that control body temperature
    NIH/NINDS R01NS094781Apr 1, 2016 - Mar 31, 2021
    Role: Principal Investigator
    Neural Dynamics Underlying Feeding
    NIH/NIDDK R01DK106399Sep 20, 2015 - Jun 30, 2020
    Role: Principal Investigator
    Sequencing Neural Circuits Controlling Thermoregulation
    NIH/NIDDK DP2DK109533Sep 15, 2015 - Jun 30, 2020
    Role: Principal Investigator
    Mechanisms of Leptin Resistance
    NIH/NIDDK R00DK083531Sep 1, 2012 - Jul 31, 2015
    Role: Principal Investigator
    Mechanisms of Leptin Resistance
    NIH/NIDDK K99DK083531Apr 5, 2009 - Mar 31, 2012
    Role: Principal Investigator

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    Collapse In The News
    Collapse Featured Publications

    Collapse Bibliographic 
    Collapse Publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help.
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    1. Tan CL, Knight Z. Regulation of Body Temperature by the Nervous System. Neuron. 2018 Apr 04; 98(1):31-48. PMID: 29621489.
      View in: PubMed
    2. Beutler LR, Knight Z. A Spotlight on Appetite. Neuron. 2018 Feb 21; 97(4):739-741. PMID: 29470967.
      View in: PubMed
    3. Leib DE, Zimmerman CA, Poormoghaddam A, Huey EL, Ahn JS, Lin YC, Tan CL, Chen Y, Knight Z. The Forebrain Thirst Circuit Drives Drinking through Negative Reinforcement. Neuron. 2017 Dec 20; 96(6):1272-1281.e4. PMID: 29268095.
      View in: PubMed
    4. Garrison JL, Knight Z. Linking smell to metabolism and aging. Science. 2017 11 10; 358(6364):718-719. PMID: 29123049.
      View in: PubMed
    5. Beutler LR, Chen Y, Ahn JS, Lin YC, Essner RA, Knight Z. Dynamics of Gut-Brain Communication Underlying Hunger. Neuron. 2017 Oct 11; 96(2):461-475.e5. PMID: 29024666.
      View in: PubMed
    6. Zimmerman CA, Leib DE, Knight Z. Neural circuits underlying thirst and fluid homeostasis. Nat Rev Neurosci. 2017 08; 18(8):459-469. PMID: 28638120.
      View in: PubMed
    7. Kharas MG, Janes MR, Scarfone VM, Lilly MB, Knight Z, Shokat KM, Fruman DA. Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells. J Clin Invest. 2017 06 01; 127(6):2438. PMID: 28569734.
      View in: PubMed
    8. Chung S, Weber F, Zhong P, Tan CL, Nguyen TN, Beier KT, Hörmann N, Chang WC, Zhang Z, Do JP, Yao S, Krashes MJ, Tasic B, Cetin A, Zeng H, Knight Z, Luo L, Dan Y. Identification of preoptic sleep neurons using retrograde labelling and gene profiling. Nature. 2017 05 25; 545(7655):477-481. PMID: 28514446.
      View in: PubMed
    9. Leib DE, Zimmerman CA, Knight Z. Thirst. Curr Biol. 2016 Dec 19; 26(24):R1260-R1265. PMID: 27997832.
      View in: PubMed
    10. Tan CL, Cooke EK, Leib DE, Lin YC, Daly GE, Zimmerman CA, Knight Z. Warm-Sensitive Neurons that Control Body Temperature. Cell. 2016 Sep 22; 167(1):47-59.e15. PMID: 27616062.
      View in: PubMed
    11. Chen Y, Lin YC, Zimmerman CA, Essner RA, Knight Z. Hunger neurons drive feeding through a sustained, positive reinforcement signal. Elife. 2016 08 24; 5. PMID: 27554486; PMCID: PMC5016090.
    12. Leib DE, Knight Z. Rapid Sensing of Dietary Amino Acid Deficiency Does Not Require GCN2. Cell Rep. 2016 08 23; 16(8):2051-2052. PMID: 27558825.
      View in: PubMed
    13. Zimmerman CA, Lin YC, Leib DE, Guo L, Huey EL, Daly GE, Chen Y, Knight Z, et al. Thirst neurons anticipate the homeostatic consequences of eating and drinking. Nature. 2016 09 29; 537(7622):680-684. PMID: 27487211.
      View in: PubMed
    14. Chen Y, Knight Z. Making sense of the sensory regulation of hunger neurons. Bioessays. 2016 Apr; 38(4):316-24. PMID: 26898524; PMCID: PMC4899083 [Available on 04/01/17].
    15. Leib DE, Knight Z. Re-examination of Dietary Amino Acid Sensing Reveals a GCN2-Independent Mechanism. Cell Rep. 2015 Nov 10; 13(6):1081-1089. PMID: 26526991; PMCID: PMC4836942.
    16. Cage TA, Chanthery Y, Chesler L, Grimmer M, Knight Z, Shokat K, Weiss WA, Gustafson WC. Downregulation of MYCN through PI3K Inhibition in Mouse Models of Pediatric Neural Cancer. Front Oncol. 2015; 5:111. PMID: 26029667; PMCID: PMC4429235.
    17. Chen Y, Lin YC, Kuo TW, Knight Z. Sensory detection of food rapidly modulates arcuate feeding circuits. Cell. 2015 Feb 26; 160(5):829-41. PMID: 25703096; PMCID: PMC4373539.
    18. Knight Z, Schmidt SF, Birsoy K, Tan K, Friedman JM. A critical role for mTORC1 in erythropoiesis and anemia. Elife. 2014 Sep 08; 3:e01913. PMID: 25201874; PMCID: PMC4179304.
    19. Tan K, Knight Z, Friedman JM. Ablation of AgRP neurons impairs adaption to restricted feeding. Mol Metab. 2014 Oct; 3(7):694-704. PMID: 25352998; PMCID: PMC4209355.
    20. Ekstrand MI, Nectow AR, Knight Z, Latcha KN, Pomeranz LE, Friedman JM. Molecular profiling of neurons based on connectivity. Cell. 2014 May 22; 157(5):1230-42. PMID: 24855954; PMCID: PMC4854627.
    21. Knight Z, Tan K, Birsoy K, Schmidt S, Garrison JL, Wysocki RW, Emiliano A, Ekstrand MI, Friedman JM. Molecular profiling of activated neurons by phosphorylated ribosome capture. Cell. 2012 Nov 21; 151(5):1126-37. PMID: 23178128; PMCID: PMC3839252.
    22. Knight Z. For a PDK1 inhibitor, the substrate matters. Biochem J. 2011 Jan 15; 433(2):e1-2. PMID: 21175429.
      View in: PubMed
    23. Knight Z, Hannan KS, Greenberg ML, Friedman JM. Hyperleptinemia is required for the development of leptin resistance. PLoS One. 2010 Jun 29; 5(6):e11376. PMID: 20613882; PMCID: PMC2894068.
    24. Williams O, Houseman BT, Kunkel EJ, Aizenstein B, Hoffman R, Knight Z, Shokat KM. Discovery of dual inhibitors of the immune cell PI3Ks p110delta and p110gamma: a prototype for new anti-inflammatory drugs. Chem Biol. 2010 Feb 26; 17(2):123-34. PMID: 20189103; PMCID: PMC2858875.
    25. Knight Z, Lin H, Shokat KM. Targeting the cancer kinome through polypharmacology. Nat Rev Cancer. 2010 02; 10(2):130-7. PMID: 20094047; PMCID: PMC2880454.
    26. Knight Z. Small molecule inhibitors of the PI3-kinase family. Curr Top Microbiol Immunol. 2010; 347:263-78. PMID: 20473788.
      View in: PubMed
    27. Niedermeier M, Hennessy BT, Knight Z, Henneberg M, Hu J, Kurtova AV, Wierda WG, Keating MJ, Shokat KM, Burger JA. Isoform-selective phosphoinositide 3'-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach. Blood. 2009 May 28; 113(22):5549-57. PMID: 19318683; PMCID: PMC4580965.
    28. Feldman ME, Apsel B, Uotila A, Loewith R, Knight Z, Ruggero D, Shokat KM. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 2009 Feb 10; 7(2):e38. PMID: 19209957; PMCID: PMC2637922.
    29. Fan QW, Cheng C, Knight Z, Haas-Kogan D, Stokoe D, James CD, McCormick F, Shokat KM, Weiss WA. EGFR signals to mTOR through PKC and independently of Akt in glioma. Sci Signal. 2009 Jan 27; 2(55):ra4. PMID: 19176518; PMCID: PMC2793677.
    30. Mirzoeva OK, Das D, Heiser LM, Bhattacharya S, Siwak D, Gendelman R, Bayani N, Wang NJ, Neve RM, Guan Y, Hu Z, Knight Z, Feiler HS, Gascard P, Parvin B, Spellman PT, Shokat KM, Wyrobek AJ, Bissell MJ, McCormick F, Kuo WL, Mills GB, Gray JW, Korn WM. Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res. 2009 Jan 15; 69(2):565-72. PMID: 19147570; PMCID: PMC2737189.
    31. Chaisuparat R, Hu J, Jham BC, Knight Z, Shokat KM, Montaner S. Dual inhibition of PI3Kalpha and mTOR as an alternative treatment for Kaposi's sarcoma. Cancer Res. 2008 Oct 15; 68(20):8361-8. PMID: 18922908; PMCID: PMC2645787.
    32. Apsel B, Blair JA, Gonzalez B, Nazif TM, Feldman ME, Aizenstein B, Hoffman R, Williams RL, Shokat KM, Knight Z. Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem Biol. 2008 Nov; 4(11):691-9. PMID: 18849971; PMCID: PMC2880455.
    33. Torbett NE, Luna-Moran A, Knight Z, Houk A, Moasser M, Weiss W, Shokat KM, Stokoe D. A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition. Biochem J. 2008 Oct 01; 415(1):97-110. PMID: 18498248; PMCID: PMC3079392.
    34. Oda K, Okada J, Timmerman L, Rodriguez-Viciana P, Stokoe D, Shoji K, Taketani Y, Kuramoto H, Knight Z, Shokat KM, McCormick F. PIK3CA cooperates with other phosphatidylinositol 3'-kinase pathway mutations to effect oncogenic transformation. Cancer Res. 2008 Oct 01; 68(19):8127-36. PMID: 18829572.
      View in: PubMed
    35. Zhang TT, Okkenhaug K, Nashed BF, Puri KD, Knight Z, Shokat KM, Vanhaesebroeck B, Marshall AJ. Genetic or pharmaceutical blockade of p110delta phosphoinositide 3-kinase enhances IgE production. J Allergy Clin Immunol. 2008 Oct; 122(4):811-819.e2. PMID: 19014771.
      View in: PubMed
    36. Kharas MG, Janes MR, Scarfone VM, Lilly MB, Knight Z, Shokat KM, Fruman DA. Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells. J Clin Invest. 2008 Sep; 118(9):3038-50. PMID: 18704194; PMCID: PMC2515380.
    37. Zunder ER, Knight Z, Houseman BT, Apsel B, Shokat KM. Discovery of drug-resistant and drug-sensitizing mutations in the oncogenic PI3K isoform p110 alpha. Cancer Cell. 2008 Aug 12; 14(2):180-92. PMID: 18691552; PMCID: PMC2720137.
    38. Wang J, Knight Z, Fiedler D, Williams O, Shokat KM, Pearce D. Activity of the p110-alpha subunit of phosphatidylinositol-3-kinase is required for activation of epithelial sodium transport. Am J Physiol Renal Physiol. 2008 Sep; 295(3):F843-50. PMID: 18653476; PMCID: PMC2536874.
    39. Park S, Chapuis N, Bardet V, Tamburini J, Gallay N, Willems L, Knight Z, Shokat KM, Azar N, Viguié F, Ifrah N, Dreyfus F, Mayeux P, Lacombe C, Bouscary D. PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia. 2008 Sep; 22(9):1698-706. PMID: 18548104.
      View in: PubMed
    40. Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, Knight Z, Cobb BS, Cantrell D, O'Connor E, Shokat KM, Fisher AG, Merkenschlager M. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A. 2008 Jun 03; 105(22):7797-802. PMID: 18509048; PMCID: PMC2409380.
    41. Chen JS, Zhou LJ, Entin-Meer M, Yang X, Donker M, Knight Z, Weiss W, Shokat KM, Haas-Kogan D, Stokoe D. Characterization of structurally distinct, isoform-selective phosphoinositide 3'-kinase inhibitors in combination with radiation in the treatment of glioblastoma. Mol Cancer Ther. 2008 Apr; 7(4):841-50. PMID: 18413797.
      View in: PubMed
    42. Balla A, Tuymetova G, Toth B, Szentpetery Z, Zhao X, Knight Z, Shokat K, Steinbach PJ, Balla T. Design of drug-resistant alleles of type-III phosphatidylinositol 4-kinases using mutagenesis and molecular modeling. Biochemistry. 2008 Feb 12; 47(6):1599-607. PMID: 18205404.
      View in: PubMed
    43. Balla A, Kim YJ, Varnai P, Szentpetery Z, Knight Z, Shokat KM, Balla T. Maintenance of hormone-sensitive phosphoinositide pools in the plasma membrane requires phosphatidylinositol 4-kinase IIIalpha. Mol Biol Cell. 2008 Feb; 19(2):711-21. PMID: 18077555; PMCID: PMC2230591.
    44. Knight Z, Garrison JL, Chan K, King DS, Shokat KM. A remodelled protease that cleaves phosphotyrosine substrates. J Am Chem Soc. 2007 Sep 26; 129(38):11672-3. PMID: 17803306; PMCID: PMC2932698.
    45. Fan QW, Cheng CK, Nicolaides TP, Hackett CS, Knight Z, Shokat KM, Weiss WA. A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. Cancer Res. 2007 Sep 01; 67(17):7960-5. PMID: 17804702; PMCID: PMC2597547.
    46. Hung CH, Thomas L, Ruby CE, Atkins KM, Morris NP, Knight Z, Scholz I, Barklis E, Weinberg AD, Shokat KM, Thomas G. HIV-1 Nef assembles a Src family kinase-ZAP-70/Syk-PI3K cascade to downregulate cell-surface MHC-I. Cell Host Microbe. 2007 Apr 19; 1(2):121-33. PMID: 18005690.
      View in: PubMed
    47. Knight Z, Shokat KM. Chemically targeting the PI3K family. Biochem Soc Trans. 2007 Apr; 35(Pt 2):245-9. PMID: 17371250.
      View in: PubMed
    48. Knight Z, Shokat KM. Chemical genetics: where genetics and pharmacology meet. Cell. 2007 Feb 09; 128(3):425-30. PMID: 17289560.
      View in: PubMed
    49. Knight Z, Feldman ME, Balla A, Balla T, Shokat KM. A membrane capture assay for lipid kinase activity. Nat Protoc. 2007; 2(10):2459-66. PMID: 17947987; PMCID: PMC2919233.
    50. Tóth B, Balla A, Ma H, Knight Z, Shokat KM, Balla T. Phosphatidylinositol 4-kinase IIIbeta regulates the transport of ceramide between the endoplasmic reticulum and Golgi. J Biol Chem. 2006 Nov 24; 281(47):36369-77. PMID: 17003043.
      View in: PubMed
    51. Van Keymeulen A, Wong K, Knight Z, Govaerts C, Hahn KM, Shokat KM, Bourne HR. To stabilize neutrophil polarity, PIP3 and Cdc42 augment RhoA activity at the back as well as signals at the front. J Cell Biol. 2006 Jul 31; 174(3):437-45. PMID: 16864657; PMCID: PMC2064239.
    52. Fan QW, Knight Z, Goldenberg DD, Yu W, Mostov KE, Stokoe D, Shokat KM, Weiss WA. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell. 2006 May; 9(5):341-9. PMID: 16697955; PMCID: PMC2925230.
    53. Knight Z, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B, Balla T, Weiss WA, Williams RL, Shokat KM. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell. 2006 May 19; 125(4):733-47. PMID: 16647110; PMCID: PMC2946820.
    54. Sturgeon CM, Knight Z, Shokat KM, Roberge M. Effect of combined DNA repair inhibition and G2 checkpoint inhibition on cell cycle progression after DNA damage. Mol Cancer Ther. 2006 Apr; 5(4):885-92. PMID: 16648558.
      View in: PubMed
    55. Knight Z, Shokat KM. Features of selective kinase inhibitors. Chem Biol. 2005 Jun; 12(6):621-37. PMID: 15975507.
      View in: PubMed
    56. Alaimo PJ, Knight Z, Shokat KM. Targeting the gatekeeper residue in phosphoinositide 3-kinases. Bioorg Med Chem. 2005 Apr 15; 13(8):2825-36. PMID: 15781393.
      View in: PubMed
    57. Knight Z, Chiang GG, Alaimo PJ, Kenski DM, Ho CB, Coan K, Abraham RT, Shokat KM. Isoform-specific phosphoinositide 3-kinase inhibitors from an arylmorpholine scaffold. Bioorg Med Chem. 2004 Sep 01; 12(17):4749-59. PMID: 15358300.
      View in: PubMed
    58. Knight Z, Schilling B, Row RH, Kenski DM, Gibson BW, Shokat KM. Phosphospecific proteolysis for mapping sites of protein phosphorylation. Nat Biotechnol. 2003 Sep; 21(9):1047-54. PMID: 12923550.
      View in: PubMed
    59. Tzfati Y, Knight Z, Roy J, Blackburn EH. A novel pseudoknot element is essential for the action of a yeast telomerase. Genes Dev. 2003 Jul 15; 17(14):1779-88. PMID: 12832393; PMCID: PMC196185.
    60. Knight Z. Another possible mechanism of resistance to STI571. Blood. 2000 Dec 01; 96(12):4003-5. PMID: 11186275.
      View in: PubMed
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