Zachary Knight, PhD

Professor
Physiology
+1 415 502-2011

We study the connection between physiology and behavior. Our goal is to understand how the brain senses the needs of the body – such as the need for food or water or warmth – and then generates specific behavioral responses that restore physiologic balance. 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.

Publications: 

Dopamine subsystems that track internal states.

Nature

Grove JCR, Gray LA, La Santa Medina N, Sivakumar N, Ahn JS, Corpuz TV, Berke JD, Kreitzer AC, Knight ZA

Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat.

eLife

Beutler LR, Corpuz TV, Ahn JS, Kosar S, Song W, Chen Y, Knight ZA

Soma-Targeted Imaging of Neural Circuits by Ribosome Tethering.

Neuron

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

Zimmerman CA, Knight ZA

Genetic Identification of Vagal Sensory Neurons That Control Feeding.

Cell

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

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

Zimmerman CA, Huey EL, Ahn JS, Beutler LR, Tan CL, Kosar S, Bai L, Chen Y, Corpuz TV, Madisen L, Zeng H, Knight ZA

A Spotlight on Appetite.

Neuron

Beutler LR, Knight ZA

The Forebrain Thirst Circuit Drives Drinking through Negative Reinforcement.

Neuron

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.)

Garrison JL, Knight ZA

Dynamics of Gut-Brain Communication Underlying Hunger.

Neuron

Beutler LR, Chen Y, Ahn JS, Lin YC, Essner RA, Knight ZA

Neural circuits underlying thirst and fluid homeostasis.

Nature reviews. Neuroscience

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

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

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

Leib DE, Zimmerman CA, Knight ZA

Warm-Sensitive Neurons that Control Body Temperature.

Cell

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

Chen Y, Lin YC, Zimmerman CA, Essner RA, Knight ZA

Thirst neurons anticipate the homeostatic consequences of eating and drinking.

Nature

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

Chen Y, Knight ZA

Downregulation of MYCN through PI3K Inhibition in Mouse Models of Pediatric Neural Cancer.

Frontiers in oncology

Cage TA, Chanthery Y, Chesler L, Grimmer M, Knight Z, Shokat K, Weiss WA, Gustafson WC

A critical role for mTORC1 in erythropoiesis and anemia.

eLife

Knight ZA, Schmidt SF, Birsoy K, Tan K, Friedman JM

Ablation of AgRP neurons impairs adaption to restricted feeding.

Molecular metabolism

Tan K, Knight ZA, Friedman JM

Molecular profiling of neurons based on connectivity.

Cell

Ekstrand MI, Nectow AR, Knight ZA, Latcha KN, Pomeranz LE, Friedman JM

Molecular profiling of activated neurons by phosphorylated ribosome capture.

Cell

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

Knight ZA

Hyperleptinemia is required for the development of leptin resistance.

PloS one

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

Williams O, Houseman BT, Kunkel EJ, Aizenstein B, Hoffman R, Knight ZA, Shokat KM

Targeting the cancer kinome through polypharmacology.

Nature reviews. Cancer

Knight ZA, Lin H, Shokat KM

Small molecule inhibitors of the PI3-kinase family.

Current topics in microbiology and immunology

Knight ZA

Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2.

PLoS biology

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

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

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

Dual inhibition of PI3Kalpha and mTOR as an alternative treatment for Kaposi's sarcoma.

Cancer research

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

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

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

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

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

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

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

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

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

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

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

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

Balla A, Kim YJ, Varnai P, Szentpetery Z, Knight Z, Shokat KM, Balla T

A remodelled protease that cleaves phosphotyrosine substrates.

Journal of the American Chemical Society

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

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

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

Knight ZA, Shokat KM

A membrane capture assay for lipid kinase activity.

Nature protocols

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

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

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

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

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

Sturgeon CM, Knight ZA, Shokat KM, Roberge M

Features of selective kinase inhibitors.

Chemistry & biology

Knight ZA, Shokat KM

Targeting the gatekeeper residue in phosphoinositide 3-kinases.

Bioorganic & medicinal chemistry

Alaimo PJ, Knight ZA, Shokat KM

Isoform-specific phosphoinositide 3-kinase inhibitors from an arylmorpholine scaffold.

Bioorganic & medicinal chemistry

Knight ZA, Chiang GG, Alaimo PJ, Kenski DM, Ho CB, Coan K, Abraham RT, Shokat KM

Phosphospecific proteolysis for mapping sites of protein phosphorylation.

Nature biotechnology

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

Tzfati Y, Knight Z, Roy J, Blackburn EH