Jha Laboratory

Laboratory Focus

Our laboratory focuses on developing a precision medicine approach to clinically important secondary injury processes like brain swelling and hemorrhage progression after acute brain injury. We are interested in these pathways because they are commonly encountered clinically and have a devastating impact on death and disability after multiple different types of acute brain injuries like traumatic brain injury (TBI), subarachnoid haemorrhage, and stroke. Our translational work in preclinical and clinical models spans a spectrum of single cell research, human biofluid markers, imaging, and genetics. One key focus of our laboratory has been using a translational approach to advance the understanding of the promising sulfonylurea-receptor-1 (SUR1) pathway in acute brain injury.

We are grateful collaborate on these projects with several phenomenal research groups and consortiums globally, including the University of Pittsburgh, Arizona State University, University of California – San Francisco, GAIN, TRACK-TBI, and CENTER-TBI.

Active Research Projects

The host response to TBI is highly individual and responsible for a large proportion of outcome variability. This includes several secondary injury processes like cerebral edema, intracranial hypertension, and contusion expansion that are key determinants of both survival and disability after TBI. Our research seeks to understand if and how genetic variability affects these processes.

We are evaluating single nucleotide polymorphisms, epigenetic, as well as gene expression. Initial work focused on SUR1-related pathways and has expanded to include both unbiased and Bayesian assessments.

Related Publications

Jha RM, Zusman BE, Puccio AM, Okonkwo DO, Pease M, Desai SM, Leach M, Conley YP, Kochanek PM. Genetic Variants Associated With Intraparenchymal Hemorrhage Progression After Traumatic Brain Injury. JAMA Netw Open. 2021 Jul 1;4(7):e2116839. doi: 10.1001/jamanetworkopen.2021.16839. PMID: 34309670; PMCID: PMC8314141.
Jha RM, Desai SM, Zusman BE, Koleck TA, Puccio AM, Okonkwo DO, Park SY, Shutter LA, Kochanek PM, Conley YP. Downstream TRPM4 Polymorphisms Are Associated with Intracranial Hypertension and Statistically Interact with ABCC8 Polymorphisms in a Prospective Cohort of Severe Traumatic Brain Injury. J Neurotrauma. 2019 Jun;36(11):1804-1817. doi: 10.1089/neu.2018.6124. Epub 2019 Feb 1. PMID: 30484364; PMCID: PMC6551973.
Liu D, Zusman BE, Shaffer JR, Li Y, Arockiaraj AI, Liu S, Weeks DE, Desai SM, Kochanek PM, Puccio AM, Okonkwo DO, Conley YP, Jha RM. Decreased DNA Methylation of RGMA is Associated with Intracranial Hypertension After Severe Traumatic Brain Injury: An Exploratory Epigenome-Wide Association Study. Neurocrit Care. 2022 Aug;37(1):26-37. doi: 10.1007/s12028-021-01424-9. Epub 2022 Jan 13. PMID: 35028889; PMCID: PMC9287123.
Jha RM, Koleck TA, Puccio AM, Okonkwo DO, Park SY, Zusman BE, Clark RSB, Shutter LA, Wallisch JS, Empey PE, Kochanek PM, Conley YP. Regionally clustered ABCC8 polymorphisms in a prospective cohort predict cerebral oedema and outcome in severe traumatic brain injury. J Neurol Neurosurg Psychiatry. 2018 Nov;89(11):1152-1162. doi: 10.1136/jnnp-2017-317741. Epub 2018 Apr 19. PMID: 29674479; PMCID: PMC6181785.
Jha RM, Elmer J, Zusman BE, Desai S, Puccio AM, Okonkwo DO, Park SY, Shutter LA, Wallisch JS, Conley YP, Kochanek PM. Intracranial Pressure Trajectories: A Novel Approach to Informing Severe Traumatic Brain Injury Phenotypes. Crit Care Med. 2018 Nov;46(11):1792-1802. doi: 10.1097/CCM.0000000000003361. PMID: 30119071; PMCID: PMC6185785.
Jha RM, Puccio AM, Okonkwo DO, Zusman BE, Park SY, Wallisch J, Empey PE, Shutter LA, Clark RS, Kochanek PM, Conley YP. ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI. Neurocrit Care. 2017 Apr;26(2):213-224. doi: 10.1007/s12028-016-0309-z. PMID: 27677908; PMCID: PMC5550833.
Jha RM. Monogenic Stroke-Can We Overcome Nature With Nurture? JAMA Neurol. 2022 Dec 1;79(12):1229-1231. doi: 10.1001/jamaneurol.2022.3994. PMID: 36300344.

We leverage known mechanisms of underlying pathobiology (for example SUR1) to evaluate and develop prognostic and predictive biofluid and imaging markers of related mechanistic endotypes (like hemorrhage progression) and thereby advance precision medicine. We also are actively evaluating sex- and age-based differences in pathophysiology using in vitro cell-based experiments, organoid models, and clinical biofluids from several types of acute brain injury with a focus on TBI and aneurysmal subarachnoid haemorrhage.

Related Publications

Zusman BE, Wu Y, Kochanek PM, Vagni VE, Janesko-Feldman K, Gerzanich V, Simard JM, Karahalios K, Mihaljevic S, Raikwar S, Rani A, Rulney J, Desai SM, Catapano J, Jha RM. Precision Effects of Glibenclamide on MRI Endophenotypes in Clinically Relevant Murine Traumatic Brain Injury. Crit Care Med. 2023 Feb 1;51(2):e45-e59. doi: 10.1097/CCM.0000000000005749. Epub 2022 Dec 16. PMID: 36661464; PMCID: PMC9848216.
Zusman BE, Kochanek PM, Bell MJ, Adelson PD, Wisniewski SR, Au AK, Clark RSB, Bayır H, Janesko-Feldman K, Jha RM. Cerebrospinal Fluid Sulfonylurea Receptor-1 is Associated with Intracranial Pressure and Outcome after Pediatric TBI: An Exploratory Analysis of the Cool Kids Trial. J Neurotrauma. 2021 Jun 15;38(12):1615-1619. doi: 10.1089/neu.2020.7501. Epub 2021 Feb 16. PMID: 33430695; PMCID: PMC8165477.
Jha RM, Puccio AM, Chou SH, Chang CH, Wallisch JS, Molyneaux BJ, Zusman BE, Shutter LA, Poloyac SM, Janesko-Feldman KL, Okonkwo DO, Kochanek PM. Sulfonylurea Receptor-1: A Novel Biomarker for Cerebral Edema in Severe Traumatic Brain Injury. Crit Care Med. 2017 Mar;45(3):e255-e264. doi: 10.1097/CCM.0000000000002079. PMID: 27845954; PMCID: PMC5550829.
Jha RM, Simard JM. Glibenclamide for Brain Contusions: Contextualizing a Promising Clinical Trial Design that Leverages an Imaging-Based TBI Endotype. Neurotherapeutics. 2023 Jun 12. doi: 10.1007/s13311-023-01389-x. Epub ahead of print. PMID: 37306928.
Cummings J, Wu YL, Dixon CE, Henchir J, Simard JM, Panigrahy A, Kochanek PM, Jha RM, Aneja RK. Abcc8 (sulfonylurea receptor-1) knockout mice exhibit reduced axonal injury, cytotoxic edema and cognitive dysfunction vs. wild-type in a cecal ligation and puncture model of sepsis. J Neuroinflammation. 2023 Jan 21;20(1):12. doi: 10.1186/s12974-023-02692-2. PMID: 36681815; PMCID: PMC9862964.
DeKosky ST, Kochanek PM, Valadka AB, Clark RSB, Chou SH, Au AK, Horvat C, Jha RM, Mannix R, Wisniewski SR, Wintermark M, Rowell SE, Welch RD, Lewis L, House S, Tanzi RE, Smith DR, Vittor AY, Denslow ND, Davis MD, Glushakova OY, Hayes RL. Blood Biomarkers for Detection of Brain Injury in COVID-19 Patients. J Neurotrauma. 2021 Jan 1;38(1):1-43. doi: 10.1089/neu.2020.7332. Epub 2020 Nov 11. PMID: 33115334; PMCID: PMC7757533.
Jha RM, Kochanek PM. A Precision Medicine Approach to Cerebral Edema and Intracranial Hypertension after Severe Traumatic Brain Injury: Quo Vadis? Curr Neurol Neurosci Rep. 2018 Nov 7;18(12):105. doi: 10.1007/s11910-018-0912-9. PMID: 30406315; PMCID: PMC6589108.
Jha R, Battey TW, Pham L, Lorenzano S, Furie KL, Sheth KN, Kimberly WT. Fluid-attenuated inversion recovery hyperintensity correlates with matrix metalloproteinase-9 level and hemorrhagic transformation in acute ischemic stroke. Stroke. 2014 Apr;45(4):1040-5. doi: 10.1161/STROKEAHA.113.004627. Epub 2014 Mar 11. PMID: 24619394; PMCID: PMC3970574.

We use preclinical models of controlled cortical impact (CCI), CCI with hemorrhagic shock, and mild-repetitive closed head injury to model clinically relevant scenarios of TBI, such as contusion or repeated athletic injuries. These models are used to study important downstream pathophysiological effects (cerebral edema, intracranial hypertension, hemorrhage progression) as well as evaluate treatments. As with our clinical research, we are actively investigating sex- and age- based differences at multiple levels: single cell, imaging, protein expression, and behavioural and cognitive outcomes.

Related Publications

Jha RM, Rajasundaram D, Sneiderman C, Schlegel BT, O’Brien C, Xiong Z, Janesko-Feldman K, Trivedi R, Vagni V, Zusman BE, Catapano JS, Eberle A, Desai SM, Jadhav AP, Mihaljevic S, Miller M, Raikwar S, Rani A, Rulney J, Shahjouie S, Raphael I, Kumar A, Phuah CL, Winkler EA, Simon DW, Kochanek PM, Kohanbash G. A single-cell atlas deconstructs heterogeneity across multiple models in murine traumatic brain injury and identifies novel cell-specific targets. Neuron. 2024 Jul 11:S0896-6273(24)00456-2. doi: 10.1016/j.neuron.2024.06.021. Epub ahead of print. PMID: 39019041.
Jha RM, Mondello S, Bramlett HM, Dixon CE, Shear DA, Dietrich WD, Wang KKW, Yang Z, Hayes RL, Poloyac SM, Empey PE, Lafrenaye AD, Yan HQ, Carlson SW, Povlishock JT, Gilsdorf JS, Kochanek PM. Glibenclamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy. J Neurotrauma. 2021 Mar;38(5):628-645. doi: 10.1089/neu.2020.7421. Epub 2020 Dec 18. PMID: 33203303; PMCID: PMC8418525.
Tata S, Zusman BE, Kochanek PM, Gerzanich V, Kwon MS, Woo SK, Clark RSB, Janesko-Feldman K, Vagni VA, Simard JM, Jha RM. Abcc8 (Sulfonylurea Receptor-1) Impact on Brain Atrophy after Traumatic Brain Injury Varies by Sex. J Neurotrauma. 2021 Sep 1;38(17):2473-2485. doi: 10.1089/neu.2021.0105. Epub 2021 Jun 25. PMID: 33940936; PMCID: PMC8403186.
Zusman BE, Kochanek PM, Bailey ZS, Leung LY, Vagni VA, Okonkwo DO, Puccio AM, Shutter LA, Janesko-Feldman KL, Gilsdorf JS, Shear DA, Jha RM. Multifaceted Benefit of Whole Blood Versus Lactated Ringer’s Resuscitation After Traumatic Brain Injury and Hemorrhagic Shock in Mice. Neurocrit Care. 2021 Jun;34(3):781-794. doi: 10.1007/s12028-020-01084-1. Epub 2020 Sep 4. PMID: 32886294; PMCID: PMC8054986.
Jha RM, Molyneaux BJ, Jackson TC, Wallisch JS, Park SY, Poloyac S, Vagni VA, Janesko-Feldman KL, Hoshitsuki K, Minnigh MB, Kochanek PM. Glibenclamide Produces Region-Dependent Effects on Cerebral Edema in a Combined Injury Model of Traumatic Brain Injury and Hemorrhagic Shock in Mice. J Neurotrauma. 2018 Sep 1;35(17):2125-2135. doi: 10.1089/neu.2016.4696. Epub 2018 Jun 6. PMID: 29648981; PMCID: PMC6098411.
Stokum JA, Shim B, Negoita S, Tsymbalyuk N, Tsymbalyuk O, Ivanova S, Keledjian K, Bryan J, Blaustein MP, Jha RM, Kahle KT, Gerzanich V, Simard JM. Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke. Sci Signal. 2023 Jun 6;16(788):eadd6364. doi: 10.1126/scisignal.add6364. Epub 2023 Jun 6. PMID: 37279286.
Zusman BE, Dixon CE, Jha RM, Vagni VA, Henchir JJ, Carlson SW, Janesko-Feldman KL, Bailey ZS, Shear DA, Gilsdorf JS, Kochanek PM. Choice of Whole Blood versus Lactated Ringer’s Resuscitation Modifies the Relationship between Blood Pressure Target and Functional Outcome after Traumatic Brain Injury plus Hemorrhagic Shock in Mice. J Neurotrauma. 2021 Oct 15;38(20):2907-2917. doi: 10.1089/neu.2021.0157. Epub 2021 Sep 15. PMID: 34269621; PMCID: PMC8672104.