Research Summary

The Knox Lab research program investigates the role of peripheral nerves in controlling epithelial organ development, regeneration, and chronic disease (autoimmune disease, aging, cancer). To explore these areas, we utilize a multiorgan approach that includes the salivary glands and cornea. Our experimental approach employs a bevy of tools that define cell identity, cell-cell relationships and cell/tissue behavior during development and response to injury and regenerative cues including mouse genetics, single cell/bulk RNA sequencing, organoids, atomic force microscopy, ex vivo organ culture, hydrogel synthesis (mechanical, physical and biological testing etc.) and high-resolution imaging. Using this strategy, we have discovered essential functions of peripheral nerves in regulating stem cell maintenance, differentiation and maturation, tissue morphogenesis and regeneration, and cell lineage outcomes. We have also uncovered multiple aspects of nerve-epithelial cell interactions and factors that drive reinnervation. Importantly, our basic research has led to the initiation of translational projects. For example, based on our recent discovery of a nerve-derived factor that promotes glandular repair after radiation-induced damage, we designed a drug-hydrogel system that provides local penetration of irradiated tissue for achieving long-term functional and structural regeneration. This therapeutic product has the potential to regenerate the salivary glands of patients who have received radiotherapy for head and neck cancer, an off target injury for which there are no regenerative therapies, and poor palliative therapies. These studies are funded by the CDOCTOR/NIDCR program and the California Institute for Regenerative Medicine translational award (TRAN1). We have conducted a pre-IND and are currently performing a pre-clinical trial in 2 large animal models (dog and rabbit) to meet the needs of the FDA for clinical translation.

Research Funding

  • September 1, 2021 - July 31, 2026 - Lacritin Regulation of Homeostasis and Ocular Surface Health , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01EY032956
  • August 1, 2021 - July 31, 2026 - Defining mechanisms driving dry eye disease progression , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01EY033040
  • September 18, 2018 - June 30, 2026 - Defining mechanisms driving salivary gland regeneration , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R35DE028255
  • September 30, 2017 - June 30, 2021 - Autonomic regulation of lacrimal stem cells , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01EY027392
  • August 1, 2015 - June 30, 2021 - Defining the role of the nervous system in aqueous-deficient dry eye , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01EY025980
  • September 30, 2016 - July 31, 2020 - Defining the role of immune-neuronal crosstalk in dry eye disease , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01EY026492
  • February 1, 2019 - January 31, 2020 - 2018 Salivary Glands and Exocrine Biology Gordon Research Conference and Seminar , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R13DE028494
  • April 1, 2014 - December 31, 2018 - Neuronal regulation of salivary stem cells , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01DE024188
  • April 1, 2016 - March 31, 2018 - Impact of aging on salivary stem cells and organ regeneration , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21DE025736
  • May 1, 2016 - April 30, 2017 - 2016 Proteoglycans Gordon Research Conference & Gordon Research Seminar , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R13AR069957
  • January 24, 2012 - December 31, 2015 - Neuronal-epithelial interactions that regulate mouse salivary gland development , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R00DE018969
  • July 20, 2012 - June 30, 2015 - Salivary gland repair and regeneration via Schwann cell-nerve interactions , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21DE022951

Education

University of New South Wales, Sydney, Australia, Ph.D., 4/2002, Biomedical Engineering
University of New South Wales, Sydney, Australia, B.S (Hon), 4/1998, Biochemistry

Honors & Awards

  • 1998
    Pacific Dunlop Postgraduate Scholarship
  • 1998
    Australian Postgraduate Award (APA)
  • 2005
    Australian Post-Doctoral Industrial Fellowship (APDI)
  • 2005
    UNSW Faculty of Engineering Research Grant
  • 2008
    NIH Pathway to Independence Award (K99/R00)
  • 2008
    Pathway to Independence Award (K99/R00)

Selected Publications

  1. Li J, Sun B, Tan LX, Griffin N, Niknezhad SV, Yu C, Berthoin L, Cruz-Pacheco N, Mohabbat S, Sinada H, Efraim Y, Chen FYT, An L, Gaylord EA, Bahney CS, Lombaert IMA, Knox SM. Rescue of non-healing, degenerative salivary glands by cholinergic-calcium signaling. bioRxiv. 2025 Feb 28.  View on PubMed
  2. Efraim Y, Chen FYT, Niknezhad SV, Pham D, Cheong KN, An L, Sinada H, McNamara NA, Knox SM. Rebuilding the autoimmune-damaged corneal stroma through topical lubrication. bioRxiv. 2024 Dec 03.  View on PubMed
  3. Delcroix V, Mauduit O, Lee HS, Ivanova A, Umazume T, Knox SM, de Paiva CS, Dartt DA, Makarenkova HP. The First Transcriptomic Atlas of the Adult Lacrimal Gland Reveals Epithelial Complexity and Identifies Novel Progenitor Cells in Mice. Cells. 2023 05 21; 12(10).  View on PubMed
  4. Li J, Sudiwala S, Berthoin L, Mohabbat S, Gaylord EA, Sinada H, Cruz Pacheco N, Chang JC, Jeon O, Lombaert IMA, May AJ, Alsberg E, Bahney CS, Knox SM. Long-term functional regeneration of radiation-damaged salivary glands through delivery of a neurogenic hydrogel. Sci Adv. 2022 Dec 21; 8(51):eadc8753.  View on PubMed
  5. May AJ, Mattingly AJ, Gaylord EA, Griffin N, Sudiwala S, Cruz-Pacheco N, Emmerson E, Mohabbat S, Nathan S, Sinada H, Lombaert IMA, Knox SM. Neuronal-epithelial cross-talk drives acinar specification via NRG1-ERBB3-mTORC2 signaling. Dev Cell. 2022 11 21; 57(22):2550-2565.e5.  View on PubMed
  6. Efraim Y, Chen FYT, Cheong KN, Gaylord EA, McNamara NA, Knox SM. A synthetic tear protein resolves dry eye through promoting corneal nerve regeneration. Cell Rep. 2022 08 30; 40(9):111307.  View on PubMed
  7. Pajic P, Shen S, Qu J, May AJ, Knox S, Ruhl S, Gokcumen O. A mechanism of gene evolution generating mucin function. Sci Adv. 2022 08 26; 8(34):eabm8757.  View on PubMed
  8. Viswanathan V, Cao H, Saiki J, Jiang D, Mattingly A, Nambiar D, Bloomstein J, Li Y, Jiang S, Chamoli M, Sirjani D, Kaplan M, Holsinger FC, Liang R, Von Eyben R, Jiang H, Guan L, Lagory E, Feng Z, Nolan G, Ye J, Denko N, Knox S, Rosen DM, Le QT. Aldehyde dehydrogenase 3A1 deficiency leads to mitochondrial dysfunction and impacts salivary gland stem cell phenotype. PNAS Nexus. 2022 May; 1(2):pgac056.  View on PubMed
  9. Khan S, Fitch S, Knox S, Arora R. Exocrine gland structure-function relationships. Development. 2022 01 01; 149(1).  View on PubMed
  10. Nnabue OE, Pletcher SD, Gurrola JG, Goldberg AN, Jordan KM, Knox SM, May AJ. Septum submucosal glands exhibit aberrant morphology and reduced mucin production in chronic rhinosinusitis. Int Forum Allergy Rhinol. 2021 10; 11(10):1443-1451.  View on PubMed
  11. Saitou M, Gaylord EA, Xu E, May AJ, Neznanova L, Nathan S, Grawe A, Chang J, Ryan W, Ruhl S, Knox SM, Gokcumen O. Functional Specialization of Human Salivary Glands and Origins of Proteins Intrinsic to Human Saliva. Cell Rep. 2020 11 17; 33(7):108402.  View on PubMed
  12. Efraim Y, Chen FYT, Stashko C, Cheong KN, Gaylord E, McNamara N, Knox SM. Alterations in corneal biomechanics underlie early stages of autoimmune-mediated dry eye disease. J Autoimmun. 2020 11; 114:102500.  View on PubMed
  13. SEAN DE LA O, LAUREN BYRNES, DANIEL M. WONG, SARAH KNOX, JULIE B. SNEDDON. 2155-P: Peripheral Nervous System Innervation of the Developing Pancreas. Diabetes. 2019 Jun 1; 68(Supplement 1):2155-p.  View on PubMed
  14. Sudiwala S, Knox SM. The emerging role of cranial nerves in shaping craniofacial development. Genesis. 2019 01; 57(1):e23282.  View on PubMed
  15. Chen FY, Gaylord E, McNamara N, Knox S. Deciphering Molecular and Phenotypic Changes Associated with Early Autoimmune Disease in the Aire-Deficient Mouse Model of Sjögren's Syndrome. Int J Mol Sci. 2018 Nov 17; 19(11).  View on PubMed
  16. May AJ, Cruz-Pacheco N, Emmerson E, Gaylord EA, Seidel K, Nathan S, Muench MO, Klein OD, Knox SM. Diverse progenitor cells preserve salivary gland ductal architecture after radiation-induced damage. Development. 2018 11 05; 145(21).  View on PubMed
  17. Byrnes LE, Wong DM, Subramaniam M, Meyer NP, Gilchrist CL, Knox SM, Tward AD, Ye CJ, Sneddon JB. Lineage dynamics of murine pancreatic development at single-cell resolution. Nat Commun. 2018 09 25; 9(1):3922.  View on PubMed
  18. Saiki JP, Cao H, Van Wassenhove LD, Viswanathan V, Bloomstein J, Nambiar DK, Mattingly AJ, Jiang D, Chen CH, Stevens MC, Simmons AL, Park HS, von Eyben R, Kool ET, Sirjani D, Knox SM, Le QT, Mochly-Rosen D. Aldehyde dehydrogenase 3A1 activation prevents radiation-induced xerostomia by protecting salivary stem cells from toxic aldehydes. Proc Natl Acad Sci U S A. 2018 06 12; 115(24):6279-6284.  View on PubMed
  19. Emmerson E, Knox SM. Salivary gland stem cells: A review of development, regeneration and cancer. Genesis. 2018 05; 56(5):e23211.  View on PubMed
  20. Emmerson E, May AJ, Berthoin L, Cruz-Pacheco N, Nathan S, Mattingly AJ, Chang JL, Ryan WR, Tward AD, Knox SM. Salivary glands regenerate after radiation injury through SOX2-mediated secretory cell replacement. EMBO Mol Med. 2018 03; 10(3).  View on PubMed

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