Zachary Knight, PhD
Professor
Physiology
School of Medicine

To address this question, we use a diverse set of experimental strategies including systems neuroscience approaches such as optogenetics, electrophysiology, and calcium imaging; molecular approaches such as RNA sequencing and mouse genetics; and classical approaches such as surgical and pharmacologic manipulations. In addition, we develop new tools that enable the molecular identification of functional populations of neurons by RNA sequencing. Through the use of these approaches, we aim to identify the molecules, cell types, interconnections, and activity patterns that drive homeostatic behaviors, and further uncover how these circuit elements become dysregulated in conditions such as obesity.

Our research is focused on three related topics: the control of hunger, thirst, and body temperature. A general principle emerging from our recent work has been the discovery that homeostatic circuits – long thought to function primarily by reacting to physiologic imbalances – instead utilize sensory cues to anticipate those physiologic changes and then adjust behavior preemptively. An ongoing interest of the lab is to understand how 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.

• Breaking down a gut-to-brain circuit that prevents malabsorption.
  Cell 2022 Jarvie BC, Knight ZA
• Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat.
  eLife 2020 Beutler LR, Corpuz TV, Ahn JS, Kosar S, Song W, Chen Y, Knight ZA
• Soma-Targeted Imaging of Neural Circuits by Ribosome Tethering.
  Neuron 2020 Chen Y, Jang H, Spratt PWE, Kosar S, Taylor DE, Essner RA, Bai L, Leib DE, Kuo TW, Lin YC, Patel M, Subkhangulova A, Kato S, Feinberg EH, Bender KJ, Knight ZA, Garrison JL
• Layers of signals that regulate appetite.
  Current opinion in neurobiology 2020 Zimmerman CA, Knight ZA
• Genetic Identification of Vagal Sensory Neurons That Control Feeding.
  Cell 2019 Bai L, Mesgarzadeh S, Ramesh KS, Huey EL, Liu Y, Gray LA, Aitken TJ, Chen Y, Beutler LR, Ahn JS, Madisen L, Zeng H, Krasnow MA, Knight ZA
• Sustained NPY signaling enables AgRP neurons to drive feeding.
  eLife 2019 Chen Y, Essner RA, Kosar S, Miller OH, Lin YC, Mesgarzadeh S, Knight ZA
• A gut-to-brain signal of fluid osmolarity controls thirst satiation.
  Nature 2019 Zimmerman CA, Huey EL, Ahn JS, Beutler LR, Tan CL, Kosar S, Bai L, Chen Y, Corpuz TV, Madisen L, Zeng H, Knight ZA
• Regulation of Body Temperature by the Nervous System.
  Neuron 2018 Tan CL, Knight ZA
• A Spotlight on Appetite.
  Neuron 2018 Beutler LR, Knight ZA
• The Forebrain Thirst Circuit Drives Drinking through Negative Reinforcement.
  Neuron 2017 Leib DE, Zimmerman CA, Poormoghaddam A, Huey EL, Ahn JS, Lin YC, Tan CL, Chen Y, Knight ZA
• Linking smell to metabolism and aging.
  Science (New York, N.Y.) 2017 Garrison JL, Knight ZA
• Dynamics of Gut-Brain Communication Underlying Hunger.
  Neuron 2017 Beutler LR, Chen Y, Ahn JS, Lin YC, Essner RA, Knight ZA
• Neural circuits underlying thirst and fluid homeostasis.
  Nature reviews. Neuroscience 2017 Zimmerman CA, Leib DE, Knight ZA
• Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells.
  The Journal of clinical investigation 2017 Kharas MG, Janes MR, Scarfone VM, Lilly MB, Knight ZA, Shokat KM, Fruman DA
• Identification of preoptic sleep neurons using retrograde labelling and gene profiling.
  Nature 2017 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 ZA, Luo L, Dan Y
• Thirst.
  Current biology : CB 2016 Leib DE, Zimmerman CA, Knight ZA
• Warm-Sensitive Neurons that Control Body Temperature.
  Cell 2016 Tan CL, Cooke EK, Leib DE, Lin YC, Daly GE, Zimmerman CA, Knight ZA
• Hunger neurons drive feeding through a sustained, positive reinforcement signal.
  eLife 2016 Chen Y, Lin YC, Zimmerman CA, Essner RA, Knight ZA
• Rapid Sensing of Dietary Amino Acid Deficiency Does Not Require GCN2.
  Cell reports 2016 Leib DE, Knight ZA
• Thirst neurons anticipate the homeostatic consequences of eating and drinking.
  Nature 2016 Zimmerman CA, Lin YC, Leib DE, Guo L, Huey EL, Daly GE, Chen Y, Knight ZA
• Making sense of the sensory regulation of hunger neurons.
  BioEssays : news and reviews in molecular, cellular and developmental biology 2016 Chen Y, Knight ZA
• Re-examination of Dietary Amino Acid Sensing Reveals a GCN2-Independent Mechanism.
  Cell reports 2015 Leib DE, Knight ZA
• Downregulation of MYCN through PI3K Inhibition in Mouse Models of Pediatric Neural Cancer.
  Frontiers in oncology 2015 Cage TA, Chanthery Y, Chesler L, Grimmer M, Knight Z, Shokat K, Weiss WA, Gustafson WC
• Sensory detection of food rapidly modulates arcuate feeding circuits.
  Cell 2015 Chen Y, Lin YC, Kuo TW, Knight ZA
• A critical role for mTORC1 in erythropoiesis and anemia.
  eLife 2014 Knight ZA, Schmidt SF, Birsoy K, Tan K, Friedman JM
• Ablation of AgRP neurons impairs adaption to restricted feeding.
  Molecular metabolism 2014 Tan K, Knight ZA, Friedman JM
• Molecular profiling of neurons based on connectivity.
  Cell 2014 Ekstrand MI, Nectow AR, Knight ZA, Latcha KN, Pomeranz LE, Friedman JM
• Molecular profiling of activated neurons by phosphorylated ribosome capture.
  Cell 2012 Knight ZA, Tan K, Birsoy K, Schmidt S, Garrison JL, Wysocki RW, Emiliano A, Ekstrand MI, Friedman JM
• For a PDK1 inhibitor, the substrate matters.
  The Biochemical journal 2011 Knight ZA
• Hyperleptinemia is required for the development of leptin resistance.
  PloS one 2010 Knight ZA, Hannan KS, Greenberg ML, Friedman JM
• Discovery of dual inhibitors of the immune cell PI3Ks p110delta and p110gamma: a prototype for new anti-inflammatory drugs.
  Chemistry & biology 2010 Williams O, Houseman BT, Kunkel EJ, Aizenstein B, Hoffman R, Knight ZA, Shokat KM
• Targeting the cancer kinome through polypharmacology.
  Nature reviews. Cancer 2010 Knight ZA, Lin H, Shokat KM
• Small molecule inhibitors of the PI3-kinase family.
  Current topics in microbiology and immunology 2010 Knight ZA
• 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 Niedermeier M, Hennessy BT, Knight ZA, Henneberg M, Hu J, Kurtova AV, Wierda WG, Keating MJ, Shokat KM, Burger JA
• Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2.
  PLoS biology 2009 Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM
• EGFR signals to mTOR through PKC and independently of Akt in glioma.
  Science signaling 2009 Fan QW, Cheng C, Knight ZA, Haas-Kogan D, Stokoe D, James CD, McCormick F, Shokat KM, Weiss WA
• Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition.
  Cancer research 2009 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,…
• Dual inhibition of PI3Kalpha and mTOR as an alternative treatment for Kaposi's sarcoma.
  Cancer research 2008 Chaisuparat R, Hu J, Jham BC, Knight ZA, Shokat KM, Montaner S
• Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases.
  Nature chemical biology 2008 Apsel B, Blair JA, Gonzalez B, Nazif TM, Feldman ME, Aizenstein B, Hoffman R, Williams RL, Shokat KM, Knight ZA
• A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition.
  The Biochemical journal 2008 Torbett NE, Luna-Moran A, Knight ZA, Houk A, Moasser M, Weiss W, Shokat KM, Stokoe D
• Genetic or pharmaceutical blockade of p110delta phosphoinositide 3-kinase enhances IgE production.
  The Journal of allergy and clinical immunology 2008 Zhang TT, Okkenhaug K, Nashed BF, Puri KD, Knight ZA, Shokat KM, Vanhaesebroeck B, Marshall AJ
• PIK3CA cooperates with other phosphatidylinositol 3'-kinase pathway mutations to effect oncogenic transformation.
  Cancer research 2008 Oda K, Okada J, Timmerman L, Rodriguez-Viciana P, Stokoe D, Shoji K, Taketani Y, Kuramoto H, Knight ZA, Shokat KM, McCormick F
• Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells.
  The Journal of clinical investigation 2008 Kharas MG, Janes MR, Scarfone VM, Lilly MB, Knight ZA, Shokat KM, Fruman DA
• Discovery of drug-resistant and drug-sensitizing mutations in the oncogenic PI3K isoform p110 alpha.
  Cancer cell 2008 Zunder ER, Knight ZA, Houseman BT, Apsel B, Shokat KM
• Activity of the p110-alpha subunit of phosphatidylinositol-3-kinase is required for activation of epithelial sodium transport.
  American journal of physiology. Renal physiology 2008 Wang J, Knight ZA, Fiedler D, Williams O, Shokat KM, Pearce D
• PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML.
  Leukemia 2008 Park S, Chapuis N, Bardet V, Tamburini J, Gallay N, Willems L, Knight ZA, Shokat KM, Azar N, Viguié F, Ifrah N, Dreyfus F, Mayeux P, Lacombe C, Bouscary D
• T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR.
  Proceedings of the National Academy of Sciences of the United States of America 2008 Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, Knight ZA, Cobb BS, Cantrell D, O'Connor E, Shokat KM, Fisher AG, Merkenschlager M
• Characterization of structurally distinct, isoform-selective phosphoinositide 3'-kinase inhibitors in combination with radiation in the treatment of glioblastoma.
  Molecular cancer therapeutics 2008 Chen JS, Zhou LJ, Entin-Meer M, Yang X, Donker M, Knight ZA, Weiss W, Shokat KM, Haas-Kogan D, Stokoe D
• Design of drug-resistant alleles of type-III phosphatidylinositol 4-kinases using mutagenesis and molecular modeling.
  Biochemistry 2008 Balla A, Tuymetova G, Toth B, Szentpetery Z, Zhao X, Knight ZA, Shokat K, Steinbach PJ, Balla T
• Maintenance of hormone-sensitive phosphoinositide pools in the plasma membrane requires phosphatidylinositol 4-kinase IIIalpha.
  Molecular biology of the cell 2007 Balla A, Kim YJ, Varnai P, Szentpetery Z, Knight Z, Shokat KM, Balla T
• Importance of PI3 Kinase Family for Crosstalk between Chronic Lymphocytic Leukemia B Cells and the Stromal Microenvironment: Therapeutic Implications.
  Blood 2007 Matthias T.W. Niedermeier, Justyna Rawluk, Zachary Knight, Kevan Shokat, William G. Wierda, Michael J. Keating, Jan A. Burger
• PI-103, a Dual Inhibitor of Class I Phosphatidylinositide 3-Kinase and mTOR, Has Anti-Leukemic Activity in Acute Myeloid Leukemia.
  Blood 2007 Sophie Park, Nicolas Chapuis, Valerie Bardet, Lise Willems, Jerome Tamburini, Zachary A. Knight, Kevan M. Shokat, Nabih Azar, Norbert Ifrah, Francois Dreyfus, Patrick Mayeux, Catherine Lacombe, Didier…
• A remodelled protease that cleaves phosphotyrosine substrates.
  Journal of the American Chemical Society 2007 Knight ZA, Garrison JL, Chan K, King DS, Shokat KM
• A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma.
  Cancer research 2007 Fan QW, Cheng CK, Nicolaides TP, Hackett CS, Knight ZA, Shokat KM, Weiss WA
• HIV-1 Nef assembles a Src family kinase-ZAP-70/Syk-PI3K cascade to downregulate cell-surface MHC-I.
  Cell host & microbe 2007 Hung CH, Thomas L, Ruby CE, Atkins KM, Morris NP, Knight ZA, Scholz I, Barklis E, Weinberg AD, Shokat KM, Thomas G
• Chemically targeting the PI3K family.
  Biochemical Society transactions 2007 Knight ZA, Shokat KM
• Chemical genetics: where genetics and pharmacology meet.
  Cell 2007 Knight ZA, Shokat KM
• A membrane capture assay for lipid kinase activity.
  Nature protocols 2007 Knight ZA, Feldman ME, Balla A, Balla T, Shokat KM
• Phosphatidylinositol 4-kinase IIIbeta regulates the transport of ceramide between the endoplasmic reticulum and Golgi.
  The Journal of biological chemistry 2006 Tóth B, Balla A, Ma H, Knight ZA, Shokat KM, Balla T
• To stabilize neutrophil polarity, PIP3 and Cdc42 augment RhoA activity at the back as well as signals at the front.
  The Journal of cell biology 2006 Van Keymeulen A, Wong K, Knight ZA, Govaerts C, Hahn KM, Shokat KM, Bourne HR
• A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma.
  Cancer cell 2006 Fan QW, Knight ZA, Goldenberg DD, Yu W, Mostov KE, Stokoe D, Shokat KM, Weiss WA
• A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling.
  Cell 2006 Knight ZA, 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
• Effect of combined DNA repair inhibition and G2 checkpoint inhibition on cell cycle progression after DNA damage.
  Molecular cancer therapeutics 2006 Sturgeon CM, Knight ZA, Shokat KM, Roberge M
• Knock-outs and inhibitors: one and the same?.
  Blood 2006 Zachary A. Knight, Kevan M. Shokat
• Features of selective kinase inhibitors.
  Chemistry & biology 2005 Knight ZA, Shokat KM
• Targeting the gatekeeper residue in phosphoinositide 3-kinases.
  Bioorganic & medicinal chemistry 2005 Alaimo PJ, Knight ZA, Shokat KM
• Isoform-specific phosphoinositide 3-kinase inhibitors from an arylmorpholine scaffold.
  Bioorganic & medicinal chemistry 2004 Knight ZA, Chiang GG, Alaimo PJ, Kenski DM, Ho CB, Coan K, Abraham RT, Shokat KM
• Erratum: Phosphospecific proteolysis for mapping sites of protein phosphorylation.
  Nature Biotechnology 2003 Zachary A Knight, Birgit Schilling, Richard H Row, Denise M Kenski, Bradford W Gibson, Kevan M Shokat
• Phosphospecific proteolysis for mapping sites of protein phosphorylation.
  Nature biotechnology 2003 Knight ZA, Schilling B, Row RH, Kenski DM, Gibson BW, Shokat KM
• A novel pseudoknot element is essential for the action of a yeast telomerase.
  Genes & development 2003 Tzfati Y, Knight Z, Roy J, Blackburn EH
• Another possible mechanism of resistance to STI571.
  Blood 2000 Knight ZA
• Another possible mechanism of resistance to STI571.
  Blood 2000 Zachary A. Knight