The role of hemolysis in sickle cell disease organ injury:

Hemolysis is a key characteristic of sickle cell disease (SCD) that contributes to the disease pathogenesis and clinical heterogeneity. In SCD, cell free hemoglobin and its byproducts (heme and iron) cause vasculopathy as well as a slew of clinical consequences, including liver failure. Although liver injury affects up to ~40% of hospitalized SCD patients, therapeutic approaches to prevent liver injury in SCD are limited. In the Pradhan-Sundd lab we are interested in understanding the molecular (signalling) mechanism of hemolysis induced acute and chronic liver injury. We are also investigating the processes of hepatic hemoglobin, heme, and iron clearance in SCD.

Sinusoidal endothelium driven liver directed gene therapy in hemophilia:

Hemophilia A is an X-linked recessive bleeding disorder caused by the absence of coagulation factor- VIII (FVIII). Individuals who are affected are at risk of spontaneous bleeding into joints which can be life threatening. Recent advances in liver-directed gene transfer suggest that gene therapy can successfully treat hemophilia A. FVIII is produced in the liver sinusoidal endothelial cells. Thus, liver sinusoidal endothelial cell viability and functioning are important for successful liver directed gene transfer in Hemophilia. We have recently shown liver sinusoidal endothelial maladaptive structural changes in FVIII-deficient mice and their deleterious impact on the efficacy of liver-directed gene transfer. Abnormal endothelial function was recently recognized in patients with hemophilia A. Our current research focuses on investigating the molecular mechanisms that contribute to the loss of endothelial fenestration in individuals with FVIII deficiency, and how this loss impacts liver-directed gene therapy in patients with hemophilia.

• 2020-2025, K01, NIH-NIDDK career development award. This grant is focused on understanding the molecular mechanism of sickle cell hepatic crisis.
• 2023-2024, Joan Gill Pilot Award in Hematological Research.
• 2022-2024, American Society of Hematology Junior Faculty Scholar Award. This award aims to decipher the role of P-selectin in sickle cell disease liver pathophysiology.

Bibhav Shrestha
Research Technologist

Ashley Smith
Senior Lab Manager

Click here for a full list of publications from Tirthadipa Pradhan-Sundd, PhD.

Click here to view Tirthadipa Pradhan-Sundd, PhD Google Scholar publication list.

Selected publications:

1. Kaminski T, Katoch O, Li Z, Hanway CB, Dubey RK, Alagbe A, Brzoska T, Zhang H, Sundd P, Kato GJ, Novelli EM, Pradhan-Sundd T. Impaired hemoglobin clearance by sinusoidal endothelium promotes vaso-occlusion and liver injury in sickle cell disease. Haematologica. 2023 Nov 9. doi: 10.3324/haematol.2023.283792. Online ahead of print.PMID: 37941440.
2. Katoch O,  Ungalara R, Kaminski T, Li A, Dubey RK, Burholt I, Gudapati S, Pradhan-Sundd T. Long-term l-glutamine treatment reduces hemolysis without ameliorating hepatic vasoocclusion and liver fibrosis in a mouse model of sickle cell disease.  Biomedicines 2023, 11(9), 2412;  Invited article for special issue on Sickle Cell Disease. 
3. Pradhan-Sundd T*, Kato GJ, Novelli EM. Molecular Mechanisms of Hepatic Dysfunction in Sickle Cell Disease: Lessons From The Townes Mouse Model. Am J Physiol Cell Physiol. 2022 Jun 27. doi: 10.1152/ajpcell.00175.2022. PMID: 35759437. Review. *first and corresponding author.
4. Vats R, Kaminski TW, Brzoska T, Leech JA, Tutuncuoglu E, Katoch O, Jonassaint JC, Tejero J, Novelli EM, Pradhan-Sundd T, Gladwin MT, Sundd P. Liver to lung microembolic NETs promote Gasdermin-D-dependent inflammatory lung injury in Sickle Cell Disease. Blood. 2022 Jun 23:blood.2021014552. doi: 10.1182/blood.2021014552.PMID: 35737916.
5. Kaminski TW, Ju E-M, Gudapati S, Vats R, Arshad S, Dubey RK, Katoch O, Tutuncuoglu E, Frank J, Brzoska T. Stolz DB, Watkins SC, Chan SY, Ragni MV, Novelli EM, Sundd P, Pradhan-Sundd T. Defenestrated endothelium delays liver directed gene transfer in Hemophilia A mice. Blood Advances, April 2022. PMID: 35427414.
6. Vats R, Li Z, Ju EM, Dubey RK, Kaminski TW, Watkins S, Pradhan-Sundd T. Intravital imaging reveals inflammation as a dominant pathophysiology of age-related hepatovascular changes. Am J Physiol Cell Physiol. 2022 Jan 5. doi:10.1152/ajpcell.00408.2021. PMID: 34986022.
7. Vats R, Kaminski T W, Pradhan-Sundd T. Intravital imaging of hepatic blood biliary barrier in live mice. August, 2021. Current protocols in Cytometry. 2021. PMID: 34986022.
8. Vats R, Kaminski T, Ju E-M, Brozska T, Tutuncuoglu E, Tejero J, Novelli E, Sundd P, Pradhan-Sundd T. P-selectin deficiency promotes liver senescence in sickle cell disease mice. Blood. 2021 Feb 22:blood.2020009779. PMID: 33619560.
9. Pradhan-Sundd T*, Gudapati S, Kaminski T, Ragni M. Exploring the complex role of procoagulant Factor VIII in chronic liver disease. Cellular molecular gastroenterology hepatology. Review Article. Cell Mol Gastroenterol Hepatol. 2021 Mar 8:S2352-345X(21)00052-7.PMID: 33705963.*first and corresponding author.

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