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Lloyd G. Cantley, MD

C. N. H. Long Professor of Medicine (Nephrology) and Professor of Cellular And Molecular Physiology; Vice Chair, Research; Co-director of Education, Yale Center for Clinical Investigation

Contact Information

Lloyd G. Cantley, MD

Office Location

Mailing Address

  • Nephrology

    PO Box 208029

    New Haven, CT 06520-8029

    United States

Yale Medicine

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Research Summary

Our laboratory is interested in defining the cellular pathways that regulate kidney epithelial development and repair and determining the effector proteins that mediate the changes that occur during tubule formation, injury and repair. We have found that macrophages are critical regulators of both initial injury and subsequent repair, and that cross-talk between macrophages and surviving tubular cells determines the macrophage expression profile that induces tubule repair. We have identified activation of the phosphoinositide 3-kinase and MAPK pathways as critical regulators of epithelial cell migration and morphogenesis during both development and repair.

Specialized Terms: Nephrology; Acute Kidney Injury; Physiology and integrative medical biology; Epithelial cell migration and morphogenesis; Epithelial cell adhesion; Migration; Branching tubulogenesis

Extensive Research Description

The primary focus of our laboratory is to determine the mechanisms of renal tubule development, homeostasis and repair. When the kidney is injured following ischemia or toxin exposure, the remaining epithelial cells de-differentiate, spread over the denuded basement membrane, divide, and re-arrange themselves in a specific pattern to regenerate functional tubules. This process requires a complex array of events involving rearrangement of cell shape and regulation of cell-matrix and cell-cell interactions. By examining epithelial cell adhesion, migration, and branching tubulogenesis in response to growth factors such as Hepatocyte Growth Factor and chitin's 3-like 1, we are determining the intracellular signaling events critical for tubule formation during kidney development and following injury. We have focused these efforts on the role of activation of specific MAPK isoforms as well as the PI 3-kinase in the regulation of cell morphogenesis and cell-matrix interactions.

In addition, we are examining the role of the innate immune response to kidney injury and found that macrophages home to the injured kidney and initially promote apoptosis of sublethally injured tubular cells. Subsequent macrophage accumulation includes increasing numbers of alternatively activated macrophages that promote the survival and proliferation of the remaining tubular cells to effect tubule repair. We are currently expanding this work to study human acute kidney injury and have developed the use of Imaging Mass Cytometry in the human kidney.

Coauthors

Research Interests

Epithelial Cells; Kidney; Macrophages; Morphogenesis; Nephrology; Physiology

Selected Publications

  • Polycystin 2 is increased in disease to protect against stress-induced cell death.Brill AL, Fischer TT, Walters JM, Marlier A, Sewanan LR, Wilson PC, Johnson EK, Moeckel G, Cantley LG, Campbell SG, Nerbonne JM, Chung HJ, Robert ME, Ehrlich BE. Polycystin 2 is increased in disease to protect against stress-induced cell death. Scientific Reports 2020, 10: 386. PMID: 31941974, PMCID: PMC6962458, DOI: 10.1038/s41598-019-57286-x.
  • Urine TNF-α and IL-9 for clinical diagnosis of acute interstitial nephritis.Moledina DG, Wilson FP, Pober JS, Perazella MA, Singh N, Luciano RL, Obeid W, Lin H, Kuperman M, Moeckel GW, Kashgarian M, Cantley LG, Parikh CR. Urine TNF-α and IL-9 for clinical diagnosis of acute interstitial nephritis. JCI Insight 2019, 4 PMID: 31092735, PMCID: PMC6542610, DOI: 10.1172/jci.insight.127456.
  • Development of a 2-dimensional atlas of the human kidney with imaging mass cytometry.Singh N, Avigan ZM, Kliegel JA, Shuch BM, Montgomery RR, Moeckel GW, Cantley LG. Development of a 2-dimensional atlas of the human kidney with imaging mass cytometry. JCI Insight 2019, 4 PMID: 31217358, PMCID: PMC6629112, DOI: 10.1172/jci.insight.129477.
  • Tubular GM-CSF Promotes Late MCP-1/CCR2-Mediated Fibrosis and Inflammation after Ischemia/Reperfusion Injury.Xu L, Sharkey D, Cantley LG. Tubular GM-CSF Promotes Late MCP-1/CCR2-Mediated Fibrosis and Inflammation after Ischemia/Reperfusion Injury. Journal Of The American Society Of Nephrology : JASN 2019, 30: 1825-1840. PMID: 31315923, PMCID: PMC6779361, DOI: 10.1681/ASN.2019010068.
  • Mcp1 Promotes Macrophage-Dependent Cyst Expansion in Autosomal Dominant Polycystic Kidney Disease.Cassini MF, Kakade VR, Kurtz E, Sulkowski P, Glazer P, Torres R, Somlo S, Cantley LG. Mcp1 Promotes Macrophage-Dependent Cyst Expansion in Autosomal Dominant Polycystic Kidney Disease. Journal Of The American Society Of Nephrology : JASN 2018, 29: 2471-2481. PMID: 30209078, PMCID: PMC6171277, DOI: 10.1681/ASN.2018050518.
  • Breast Regression Protein-39/Chitinase 3-Like 1 Promotes Renal Fibrosis after Kidney Injury via Activation of Myofibroblasts.Montgomery TA, Xu L, Mason S, Chinnadurai A, Lee CG, Elias JA, Cantley LG. Breast Regression Protein-39/Chitinase 3-Like 1 Promotes Renal Fibrosis after Kidney Injury via Activation of Myofibroblasts. Journal Of The American Society Of Nephrology : JASN 2017, 28: 3218-3226. PMID: 28679671, PMCID: PMC5661290, DOI: 10.1681/ASN.2017010110.
  • Development of a Targeted Urine Proteome Assay for kidney diseases.Cantley LG, Colangelo CM, Stone KL, Chung L, Belcher J, Abbott T, Cantley JL, Williams KR, Parikh CR. Development of a Targeted Urine Proteome Assay for kidney diseases. Proteomics. Clinical Applications 2016, 10: 58-74. PMID: 26220717, PMCID: PMC5003777, DOI: 10.1002/prca.201500020.
  • GM-CSF Promotes Macrophage Alternative Activation after Renal Ischemia/Reperfusion Injury.Huen SC, Huynh L, Marlier A, Lee Y, Moeckel GW, Cantley LG. GM-CSF Promotes Macrophage Alternative Activation after Renal Ischemia/Reperfusion Injury. Journal Of The American Society Of Nephrology : JASN 2015, 26: 1334-45. PMID: 25388222, PMCID: PMC4446881, DOI: 10.1681/ASN.2014060612.
  • Casein kinase 2 prevents mesenchymal transformation by maintaining Foxc2 in the cytoplasm.Golden D, Cantley LG. Casein kinase 2 prevents mesenchymal transformation by maintaining Foxc2 in the cytoplasm. Oncogene 2015, 34: 4702-12. PMID: 25486430, PMCID: PMC4459945, DOI: 10.1038/onc.2014.395.
  • Met activation is required for early cytoprotection after ischemic kidney injury.Mason S, Hader C, Marlier A, Moeckel G, Cantley LG. Met activation is required for early cytoprotection after ischemic kidney injury. Journal Of The American Society Of Nephrology : JASN 2014, 25: 329-37. PMID: 24136921, PMCID: PMC3904569, DOI: 10.1681/ASN.2013050473.
  • Hepatocyte growth factor (Hgf) stimulates low density lipoprotein receptor-related protein (Lrp) 5/6 phosphorylation and promotes canonical Wnt signaling.Koraishy FM, Silva C, Mason S, Wu D, Cantley LG. Hepatocyte growth factor (Hgf) stimulates low density lipoprotein receptor-related protein (Lrp) 5/6 phosphorylation and promotes canonical Wnt signaling. The Journal Of Biological Chemistry 2014, 289: 14341-50. PMID: 24692544, PMCID: PMC4022900, DOI: 10.1074/jbc.M114.563213.
  • The Terminator mouse is a diphtheria toxin-receptor knock-in mouse strain for rapid and efficient enrichment of desired cell lineages.Guo JK, Shi H, Koraishy F, Marlier A, Ding Z, Shan A, Cantley LG. The Terminator mouse is a diphtheria toxin-receptor knock-in mouse strain for rapid and efficient enrichment of desired cell lineages. Kidney International 2013, 84: 1041-6. PMID: 23739236, PMCID: PMC3775868, DOI: 10.1038/ki.2013.202.
  • Brg1 determines urothelial cell fate during ureter development.Weiss RM, Guo S, Shan A, Shi H, Romano RA, Sinha S, Cantley LG, Guo JK. Brg1 determines urothelial cell fate during ureter development. Journal Of The American Society Of Nephrology : JASN 2013, 24: 618-26. PMID: 23449535, PMCID: PMC3609140, DOI: 10.1681/ASN.2012090902.
  • Chitinase 3-like 1 regulates cellular and tissue responses via IL-13 receptor α2.He CH, Lee CG, Dela Cruz CS, Lee CM, Zhou Y, Ahangari F, Ma B, Herzog EL, Rosenberg SA, Li Y, Nour AM, Parikh CR, Schmidt I, Modis Y, Cantley L, Elias JA. Chitinase 3-like 1 regulates cellular and tissue responses via IL-13 receptor α2. Cell Reports 2013, 4: 830-41. PMID: 23972995, PMCID: PMC3988532, DOI: 10.1016/j.celrep.2013.07.032.
  • Chitinase-like protein Brp-39/YKL-40 modulates the renal response to ischemic injury and predicts delayed allograft function.Schmidt IM, Hall IE, Kale S, Lee S, He CH, Lee Y, Chupp GL, Moeckel GW, Lee CG, Elias JA, Parikh CR, Cantley LG. Chitinase-like protein Brp-39/YKL-40 modulates the renal response to ischemic injury and predicts delayed allograft function. Journal Of The American Society Of Nephrology : JASN 2013, 24: 309-19. PMID: 23291472, PMCID: PMC3559482, DOI: 10.1681/ASN.2012060579.
  • Increased tubular proliferation as an adaptive response to glomerular albuminuria.Guo JK, Marlier A, Shi H, Shan A, Ardito TA, Du ZP, Kashgarian M, Krause DS, Biemesderfer D, Cantley LG. Increased tubular proliferation as an adaptive response to glomerular albuminuria. Journal Of The American Society Of Nephrology : JASN 2012, 23: 429-37. PMID: 22193389, PMCID: PMC3294312, DOI: 10.1681/ASN.2011040396.
  • Distinct macrophage phenotypes contribute to kidney injury and repair.Lee S, Huen S, Nishio H, Nishio S, Lee HK, Choi BS, Ruhrberg C, Cantley LG. Distinct macrophage phenotypes contribute to kidney injury and repair. Journal Of The American Society Of Nephrology : JASN 2011, 22: 317-26. PMID: 21289217, PMCID: PMC3029904, DOI: 10.1681/ASN.2009060615.
  • Macrophages promote cyst growth in polycystic kidney disease.Karihaloo A, Koraishy F, Huen SC, Lee Y, Merrick D, Caplan MJ, Somlo S, Cantley LG. Macrophages promote cyst growth in polycystic kidney disease. Journal Of The American Society Of Nephrology : JASN 2011, 22: 1809-14. PMID: 21921140, PMCID: PMC3187181, DOI: 10.1681/ASN.2011010084.
  • Development and external validation of a diagnostic model for biopsy-proven acute interstitial nephritis using electronic health record data.Moledina DG, Eadon MT, Calderon F, Yamamoto Y, Shaw M, Perazella MA, Simonov M, Luciano R, Schwantes-An TH, Moeckel G, Kashgarian M, Kuperman M, Obeid W, Cantley LG, Parikh CR, Wilson FP. Development and external validation of a diagnostic model for biopsy-proven acute interstitial nephritis using electronic health record data. Nephrology, Dialysis, Transplantation : Official Publication Of The European Dialysis And Transplant Association - European Renal Association 2021 PMID: 34865148, DOI: 10.1093/ndt/gfab346.
  • Characterization of temporospatial distribution of renal tubular casts by nephron tracking after ischemia-reperfusion injury.Shin NS, Marlier A, Xu L, Lam T, Cantley LG, Guo JK. Characterization of temporospatial distribution of renal tubular casts by nephron tracking after ischemia-reperfusion injury. American Journal Of Physiology. Renal Physiology 2022, 322: F322-F334. PMID: 35100823, PMCID: PMC8897010, DOI: 10.1152/ajprenal.00284.2021.
  • Using Imaging Mass Cytometry to Define Cell Identities and Interactions in Human Tissues.Kakade VR, Weiss M, Cantley LG. Using Imaging Mass Cytometry to Define Cell Identities and Interactions in Human Tissues. Frontiers In Physiology 2021, 12: 817181. PMID: 35002783, PMCID: PMC8727440, DOI: 10.3389/fphys.2021.817181.
  • Mortality after acute kidney injury and acute interstitial nephritis in patients prescribed immune checkpoint inhibitor therapy.Baker ML, Yamamoto Y, Perazella MA, Dizman N, Shirali AC, Hafez N, Weinstein J, Simonov M, Testani JM, Kluger HM, Cantley LG, Parikh CR, Wilson FP, Moledina DG. Mortality after acute kidney injury and acute interstitial nephritis in patients prescribed immune checkpoint inhibitor therapy. Journal For Immunotherapy Of Cancer 2022, 10 PMID: 35354588, PMCID: PMC8968986, DOI: 10.1136/jitc-2021-004421.
  • Interferon activated gene 204 protects against bone loss in experimental periodontitis.Swanson KV, Girnary M, Alves T, Ting JP, Divaris K, Beck J, Pucinelli CM, da Silva RAB, Uyan D, Wilson JE, Seaman WT, Webster-Cyriaque J, Vias N, Jiao Y, Cantley L, Marlier A, Arnold RR, Marchesan JT. Interferon activated gene 204 protects against bone loss in experimental periodontitis. Journal Of Periodontology 2022, 93: 1366-1377. PMID: 35404474, PMCID: PMC9489626, DOI: 10.1002/JPER.21-0668.
  • Arginase-1 Is Required for Macrophage-Mediated Renal Tubule Regeneration.Shin NS, Marlier A, Xu L, Doilicho N, Linberg D, Guo J, Cantley LG. Arginase-1 Is Required for Macrophage-Mediated Renal Tubule Regeneration. Journal Of The American Society Of Nephrology : JASN 2022, 33: 1077-1086. PMID: 35577558, PMCID: PMC9161787, DOI: 10.1681/ASN.2021121548.
  • Immune-mediated tubule atrophy promotes acute kidney injury to chronic kidney disease transition.Xu L, Guo J, Moledina DG, Cantley LG. Immune-mediated tubule atrophy promotes acute kidney injury to chronic kidney disease transition. Nature Communications 2022, 13: 4892. PMID: 35986026, PMCID: PMC9391331, DOI: 10.1038/s41467-022-32634-0.
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