Current Environment: Development

Winter Weather

Snow is in the forecast. Consider switching to a virtual visit to receive care from home. Learn more>>

Dev

Research Overview

Visit the Kahle Lab

The cortex develops hand-in-glove with its cerebrospinal fluid (CSF)-filled ventricular cavities whose walls harbor neural stem cells (NSCs) destined to become mature neurons and glia. Within each ventricle, the choroid plexus (ChP), comprising the blood-CSF immune barrier, secretes a half-liter of CSF/day, delivering growth factors to proliferating NSCs and flushing wastes into the glia-lymphatic “brain-drain”. Despite its importance for brain morphogenesis and function, the biology of the ChP/CSF-ventricular system, and its interplay with NSCs at the CSF-brain interface, remains enigmatic.

The Kahle lab’s objective is to probe the molecular logic of the ChP/CSF-ventricular system by studying its dysregulation in hydrocephalus and related human CSF disorders – the most common reasons for brain surgery in children. To do this, their lab has developed multi-omic, computational, and physiological methods, including in vivo measurements of CSF dynamics and viral-mediated ChP-specific gene editing. Using these methods, they have identified a druggable kinase-regulated switch of ChP immuno-secretory function that holds potential for the treatment of multiple forms of acquired hydrocephalus (Nat Med, 2017; Cell, 2023) and (ii) discovered >10 congenital hydrocephalus (CH) disease genes, establishing a clinically-impactful “NSC paradigm” of disease (Neuron, 2018; Nat Med, 2021; Nat Neurosci, 2022; Neuron 2022).

However, the understanding of the mechanisms of the ChP’s secretory and immune-barrier functions remain rudimentary; (ii) the genetic causes of most CH cases and other CSF disorders remain unsolved; and (iii) the mechanisms by which patient mutations disrupt CSF dynamics and parenchymal function via the NSC dysregulation are poorly characterized. The Kahle lab is positioned to address these knowledge gaps by leveraging orthogonal data sets generated from several of the world’s-largest cohorts of CSF disorders (congenital hydrocephalus, Chiari I malformation, arachnoid cysts, spina bifida, and others) and patient-derived/humanized model systems. Results will elucidate fundamental aspects of human brain development; re-classify CSF disorders with a molecular nomenclature that increases precision for prognostication and treatment stratification; and catalyze the development of targeted therapies.

Research Background

Dr. Kahle is the Chief of Pediatric Neurosurgery at MGH and the Director of the MGH Developmental Brain and Spine Disorders Program, with appointments in the Department of Neurosurgery at Boston Children’s Hospital, the Division of Genetics and Genomics at Boston Children’s Hospital, and the Broad Institute of MIT and Harvard. He is a board-certified pediatric neurosurgeon and scientific principal investigator and recognized world expert in congenital anomalies of the central nervous system, including cerebrospinal fluid disorders. Dr. Kahle graduated cum laude from the University of Chicago in 1999 with degrees in Biology an Philosophy.

He received his M.D. and Ph.D. degrees from Yale School of Medicine in 2007 as part of the NIH Medical Scientist Training Program under Ph.D. mentor and human geneticist Richard Lifton. He completed neurosurgery residency training at MGH in 2014 and a post-doctoral research fellowship at Harvard University with co-mentors Stephen Elledge and David Clapham. He completed pediatric neurosurgery fellowship at Boston Children’s Hospital in 2015, where he was Shellito Staff Associate and Instructor at Harvard Medical School. Afterwards, Dr. Kahle joined the Yale School of Medicine faculty, where he was Assistant Professor of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology and Director of Neonatal and Congenital Anomaly Neurosurgery from 2016-2021.

In 2021, Dr. Kahle was recruited back to MGH to serve as the Nicholas T. Zervas Endowed Chair and Associate Professor at Harvard Medical School and Chief of Pediatric Neurosurgery at MGH. His lab, now located in the in the Charlestown Navy Yard, has discovered more than 10 human disease genes, is supported by three active primary NIH RO1 grants and other foundation funding, and trains the next generation of scientists, including physician- and neurosurgeon-scientists. Dr. Kahle has been elected to the Academy of Neurological Surgeons, American Society of Pediatric Neurosurgeons, and American Society for Clinical Investigation.

Selected Publications

  1. Kundishora AJ, Allington G, McGee S, Mekbib KY, Gainullin V, Timberlake AT, Nelson-Williams C, Kiziltug E, Smith H, Ocken J, Shohfi J, Allocco A, Duy PQ, Elsamadicy AA, Dong W, Zhao S, Wang YC, Qureshi HM, DiLuna ML, Mane S, Tikhonova IR, Fu PY, Castaldi C, López-Giráldez F, Knight JR, Furey CG, Carter BS, Haider S, Moreno-De-Luca A, Alper SL, Gunel M, Millan F, Lifton RP, Torene RI, Jin SC, Kahle KT. Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts. Nat Med. 2023 Mar;29(3):667-678. doi: 10.1038/s41591-023-02238-2. Epub 2023 Mar 6. PMID: 36879130.
  2. Robert SM, Reeves BC, Kiziltug E, Duy PQ, Karimy JK, Mansuri MS, Marlier A, Allington G, Greenberg ABW, DeSpenza T Jr, Singh AK, Zeng X, Mekbib KY, Kundishora AJ, Nelson-Williams C, Hao LT, Zhang J, Lam TT, Wilson R, Butler WE, Diluna ML, Feinberg P, Schafer DP, Movahedi K, Tannenbaum A, Koundal S, Chen X, Benveniste H, Limbrick DD Jr, Schiff SJ, Carter BS, Gunel M, Simard JM, Lifton RP, Alper SL, Delpire E, Kahle KT. The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus. Cell. 2023 Feb 16;186(4):764-785.e21. doi: 10.1016/j.cell.2023.01.017. PMID: 36803604; PMCID: PMC10069664.
  3. Duy PQ, Weise SC, Marini C, Li XJ, Liang D, Dahl PJ, Ma S, Spajic A, Dong W, Juusola J, Kiziltug E, Kundishora AJ, Koundal S, Pedram MZ, Torres-Fernández LA, Händler K, De Domenico E, Becker M, Ulas T, Juranek SA, Cuevas E, Hao LT, Jux B, Sousa AMM, Liu F, Kim SK, Li M, Yang Y, Takeo Y, Duque A, Nelson-Williams C, Ha Y, Selvaganesan K, Robert SM, Singh AK, Allington G, Furey CG, Timberlake AT, Reeves BC, Smith H, Dunbar A, DeSpenza T Jr, Goto J, Marlier A, Moreno-De-Luca A, Yu X, Butler WE, Carter BS, Lake EMR, Constable RT, Rakic P, Lin H, Deniz E, Benveniste H, Malvankar NS, Estrada-Veras JI, Walsh CA, Alper SL, Schultze JL, Paeschke K, Doetzlhofer A, Wulczyn FG, Jin SC, Lifton RP, Sestan N, Kolanus W, Kahle KT. Impaired neurogenesis alters brain biomechanics in a neuroprogenitor- based genetic subtype of congenital hydrocephalus. Nat Neurosci. 2022 Apr;25(4):458-473. doi: 10.1038/s41593-022-01043-3. Epub 2022 Apr 4. PMID: 35379995; PMCID: PMC9664907.
  4. Kundishora AJ, Peters ST, Pinard A, Duran D, Panchagnula S, Barak T, Miyagishima DF, Dong W, Smith H, Ocken J, Dunbar A, Nelson-Williams C, Haider S, Walker RL, Li B, Zhao H, Thumkeo D, Marlier A, Duy PQ, Diab NS, Reeves BC, Robert SM, Sujijantarat N, Stratman AN, Chen YH, Zhao S, Roszko I, Lu Q, Zhang B, Mane S, Castaldi C, López-Giráldez F, Knight JR, Bamshad MJ, Nickerson DA, Geschwind DH, Chen SL, Storm PB, Diluna ML, Matouk CC, Orbach DB, Alper SL, Smith ER, Lifton RP, Gunel M, Milewicz DM, Jin SC, Kahle KT. DIAPH1 Variants in Non-East Asian Patients With Sporadic Moyamoya Disease. JAMA Neurol. 2021 Aug 1;78(8):993-1003. doi: 10.1001/jamaneurol.2021.1681. PMID: 34125151; PMCID: PMC8204259.
  5. Sullivan W, Reeves BC, Duy PQ, Nelson-Williams C, Dong W, Jin SC, Kahle KT. Exome Sequencing as a Potential Diagnostic Adjunct in Sporadic Congenital Hydrocephalus. JAMA Pediatr. 2021 Mar 1;175(3):310-313. doi: 10.1001/jamapediatrics.2020.4878. PMID: 33196764; PMCID: PMC7670396.
  6. Jin SC, Dong W, Kundishora AJ, Panchagnula S, Moreno-De-Luca A, Furey CG, Allocco AA, Walker RL, Nelson-Williams C, Smith H, Dunbar A, Conine S, Lu Q, Zeng X, Sierant MC, Knight JR, Sullivan W, Duy PQ, DeSpenza T, Reeves BC, Karimy JK, Marlier A, Castaldi C, Tikhonova IR, Li B, Peña HP, Broach JR, Kabachelor EM, Ssenyonga P, Hehnly C, Ge L, Keren B, Timberlake AT, Goto J, Mangano FT, Johnston JM, Butler WE, Warf BC, Smith ER, Schiff SJ, Limbrick DD Jr, Heuer G, Jackson EM, Iskandar BJ, Mane S, Haider S, Guclu B, Bayri Y, Sahin Y, Duncan CC, Apuzzo MLJ, DiLuna ML, Hoffman EJ, Sestan N, Ment LR, Alper SL, Bilguvar K, Geschwind DH, Günel M, Lifton RP, Kahle KT. Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus. Nat Med. 2020 Nov;26(11):1754-1765. doi: 10.1038/s41591-020-1090-2. Epub 2020 Oct 19. PMID: 33077954; PMCID: PMC7871900.
  7. Duran D, Zeng X, Jin SC, Choi J, Nelson-Williams C, Yatsula B, Gaillard J, Furey CG, Lu Q, Timberlake AT, Dong W, Sorscher MA, Loring E, Klein J, Allocco A, Hunt A, Conine S, Karimy JK, Youngblood MW, Zhang J, DiLuna ML, Matouk CC, Mane S, Tikhonova IR, Castaldi C, López-Giráldez F, Knight J, Haider S, Soban M, Alper SL, Komiyama M, Ducruet AF, Zabramski JM, Dardik A, Walcott BP, Stapleton CJ, Aagaard-Kienitz B, Rodesch G, Jackson E, Smith ER, Orbach DB, Berenstein A, Bilguvar K, Vikkula M, Gunel M, Lifton RP, Kahle KT. Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation. Neuron. 2019 Feb 6;101(3):429-443.e4. doi: 10.1016/j.neuron.2018.11.041. Epub 2018 Dec 18. PMID: 30578106.
  8. Furey CG, Choi J, Jin SC, Zeng X, Timberlake AT, Nelson-Williams C, Mansuri MS, Lu Q, Duran D, Panchagnula S, Allocco A, Karimy JK, Khanna A, Gaillard JR, DeSpenza T, Antwi P, Loring E, Butler WE, Smith ER, Warf BC, Strahle JM, Limbrick DD, Storm PB, Heuer G, Jackson EM, Iskandar BJ, Johnston JM, Tikhonova I, Castaldi C, López-Giráldez F, Bjornson RD, Knight JR, Bilguvar K, Mane S, Alper SL, Haider S, Guclu B, Bayri Y, Sahin Y, Apuzzo MLJ, Duncan CC, DiLuna ML, Günel M, Lifton RP, Kahle KT. De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus. Neuron. 2018 Jul 25;99(2):302-314.e4. doi: 10.1016/j.neuron.2018.06.019. Epub 2018 Jul 5. PMID: 29983323; PMCID: PMC7839075.
  9. Furey CG, Timberlake AT, Nelson-Williams C, Duran D, Li P, Jackson EM, Kahle KT. Xp22.2 Chromosomal Duplication in Familial Intracranial Arachnoid Cyst. JAMA Neurol. 2017 Dec 1;74(12):1503-1504. doi: 10.1001/jamaneurol.2017.3399. PMID: 29052703; PMCID: PMC5822190.
  10. Karimy JK, Zhang J, Kurland DB, Theriault BC, Duran D, Stokum JA, Furey CG, Zhou X, Mansuri MS, Montejo J, Vera A, DiLuna ML, Delpire E, Alper SL, Gunel M, Gerzanich V, Medzhitov R, Simard JM, Kahle KT. Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus. Nat Med. 2017 Aug;23(8):997-1003. doi: 10.1038/nm.4361. Epub 2017 Jul 10. PMID: 28692063.