Nirav Dhanesha, PhD
Assistant Professor
Department of Pathology and Translational Pathobiology
B.Pharm (2001-2005) – North Gujarat University, India
M.Pharm (2005-2007) –Gujarat University, India.
PhD (2010-2014) – KSV University and Zydus Research Center, India
Post‐Doctoral Fellow (2014-2019)– University of Iowa
News
Research
Research
Venous thromboembolic (VTE) events including deep vein thrombosis (DVT) and pulmonary embolism (PE) occurs in up to 2 million Americans per year of which 10-30% of patients die within 30 days. The incidence of VTE increases sharply with age. Young individuals have very low VTE risk, but it increases to ∼ 1% per year in the elderly, suggesting that aging is one of the strongest and most prevalent risk factors for VTE. Similarly, patients with stroke are at a particular risk for developing VTE events, which can result into worse clinical outcome and is estimated to affect approximately 80,000 stroke patients each year in the United States.
The risk of DVT for patients who have had an acute ischemic stroke is close to that for patients undergoing major surgical procedures. While prophylactic anticoagulation reduces the rates of VTE in such high-risk patients, they only prevent approximately half of the expected VTE events. In addition, the use of anticoagulants is associated with significant risk of bleeding. These data highlight the critical need for novel and safe adjuvant treatments to reduce VTE burden in these patient population.
Our lab applies a multidisciplinary approach in stroke and thrombosis research, combining data from human samples, in vitro assay and preclinical models of stroke, venous and arterial thrombosis. With the NIH/NHLBI funded R01 and American Heart Association funded Career Development Award, we are evaluating the mechanistic role of neutrophil integrin alpha9beta1 in the pathogenesis of venous thrombosis in the setting of stroke and obesity.
Integrin α9β1 and Arterial thrombosis
Integrin α9β1, which is highly expressed on activated neutrophils, stabilizes neutrophil adhesion to the activated endothelium in synergy with β2 integrin. To understand the role of integrin α9 in arterial thrombosis we generated novel myeloid cell-specific integrin α9−/− mice (α9fl/flLysMCre+). We observed that α9fl/flLysMCre+ mice were less susceptible to arterial thrombosis in ferric chloride (FeCl3) and laser injury-induced thrombosis models with unaltered hemostasis. Neutrophil elastase-positive cells were significantly reduced in α9fl/flLysMCre+ mice concomitant with reduction in neutrophil count, myeloperoxidase levels, and red blood cells in the FeCl3 injury-induced carotid thrombus. The percentage of cells releasing NETs was significantly reduced in α9fl/flLysMCre+ mouse neutrophils stimulated with thrombin-activated platelets. Furthermore, we found a significant decrease in neutrophil-mediated platelet aggregation and cathepsin-G secretion in α9fl/flLysMCre+ mice. Transfusion of α9fl/fl neutrophils in α9fl/flLysMCre+ mice restored thrombosis similar to α9fl/fl mice. Treatment of wild-type mice with anti-integrin α9 antibody inhibited arterial thrombosis. This study identifies the potential role of integrin α9 in modulating arterial thrombosis.
Integrin α9β1 and Stroke
Using myeloid-specific α9-deficient (α9−/−) wild type (α9fl/flLysMCre+/−), hyperlipidemic (α9fl/flLysMCre+/−Apoe−/−), and aged (bone marrow chimeric) mice, we evaluated stroke outcome. Susceptibility to ischemia/reperfusion injury was evaluated at 1-, 7-, and 28-days following reperfusion in 2 models of experimental stroke: filament and embolic. We found that peripheral neutrophils displayed elevated α9 expression following stroke. Irrespective of sex, genetic deletion of α9 in myeloid cells improved short- and long-term stroke outcomes in the wild type, hyperlipidemic, and aged mice. Improved stroke outcome and enhanced survival in myeloid-specific α9−/− mice was because of marked decrease in cerebral thromboinflammatory response as evidenced by reduced fibrin, platelet thrombi, neutrophil, NETosis, and decreased phospho-NF-κB (nuclear factor-κB), TNF (tumor necrosis factor)-α, and IL (interleukin)-1β levels. α9−/− mice were less susceptible to FeCl3 injury-induced carotid artery thrombosis that was concomitant with improved regional cerebral blood flow following stroke as revealed by laser speckle imaging. Mechanistically, fibronectin containing extra domain A, a ligand for integrin α9, partially contributed to α9-mediated stroke exacerbation. Infusion of a specific anti-integrin α9 inhibitor into hyperlipidemic mice following reperfusion significantly reduced infarct volume and improved short- and long-term functional outcomes up to 28 days.
Publications
Complete List of Published Work:
https://www.ncbi.nlm.nih.gov/myncbi/1tAUTIEAQBr52/bibliography/public/
Google Scholar: https://scholar.google.co.in/citations?user=hOkiZ08AAAAJ&hl=en
Selected Publications
- Dhanesha N, Patel RB, Jain M, Kumskova M, Thedens D, Olalde H, Doddapattar P, Leira EC and Chauhan AK. Pyruvate kinase M2 regulates Neutrophil Hyperactivation and promotes Cerebral Thrombo-inflammation: Therapeutic Implications for Acute Ischemic Stroke Blood. 2021 Sep 15;blood.2021012322.
- Dhanesha N, Jain M, Doddapattar P, Undas A, Chauhan AK. Cellular fibronectin promotes deep vein thrombosis in diet-induced obese mice. J Thromb Haemost. 2021 Mar;19(3):814-821.
- Dhanesha N, Jain M, Tripathi AK, Doddapattar P, Chorawala M, Bathla G, Nayak MK, Ghatge M, Lentz SR, Kon S, Chauhan AK. Targeting Myeloid-Specific Integrin α9β1 Improves Short- and Long- Term Stroke Outcomes in Murine Models With Preexisting Comorbidities by Limiting Thrombosis and Inflammation. Circ Res. 2020 Jun 5;126(12):1779-1794.
- Dhanesha N, Schnell T, Rahmatalla S, DeShaw J, Thedens D, Parker BM, Zimmerman MB, Pieper AA, Chauhan AK, Leira EC. Low-Frequency Vibrations Enhance Thrombolytic Therapy and Improve Stroke Outcomes. Stroke. 2020 Jun;51(6):1855-1861.
- Dhanesha N, Nayak MK, Doddapattar P, Jain M, Flora GD, Kon S, Chauhan AK. Targeting myeloid-cell specific integrin α9β1 inhibits arterial thrombosis in mice. Blood. 2020 Mar 12;135(11):857- 861.
- Dhanesha N, Chorawala MR, Jain M, Bhalla A, Thedens D, Nayak M, Doddapattar P, Chauhan AK. Fn-EDA (Fibronectin Containing Extra Domain A) in the Plasma, but Not Endothelial Cells, Exacerbates Stroke Outcome by Promoting Thrombo-Inflammation. Stroke. 2019 May;50(5):1201-1209.
- Dhanesha N, Vázquez-Rosa E, Cintrón-Pérez CJ, Thedens D, Kort AJ, Chuong V, Rivera- Dompenciel AM, Chauhan AK, Leira EC, Pieper AA. Treatment with Uric Acid Reduces Infarct and Improves Neurologic Function in Female Mice After Transient Cerebral Ischemia. J Stroke Cerebrovasc Dis. 2018 May;27(5):1412-1416.
- Dhanesha N, Doddapattar P, Chorawala MR, Nayak MK, Kokame K, Staber JM, Lentz SR, Chauhan AK. ADAMTS13 Retards Progression of Diabetic Nephropathy by Inhibiting Intrarenal Thrombosis in Mice. Arterioscler Thromb Vasc Biol. 2017 Jul;37(7):1332-1338.
- Dhanesha N, Ahmad A, Prakash P, Doddapattar P, Lentz SR, Chauhan AK. Genetic Ablation of Extra Domain A of Fibronectin in Hypercholesterolemic Mice Improves Stroke Outcome by Reducing Thrombo-Inflammation. Circulation. 2015 Dec 8;132(23):2237-47.
- Dhanesha N, Prakash P, Doddapattar P, Khanna I, Pollpeter MJ, Nayak MK, Staber JM, Chauhan AK. Endothelial Cell-Derived von Willebrand Factor Is the Major Determinant That Mediates von Willebrand Factor-Dependent Acute Ischemic Stroke by Promoting Postischemic Thrombo- Inflammation. Arterioscler Thromb Vasc Biol. 2016 Sep;36(9):1829-37.
Team
Nirav Dhanesha, PhD
Principal Investigator
nirav.dhanesha@lsuhs.edu
Our lab’s long-term research goals are to elucidate the mechanistic basis for thrombo-inflammation in the setting of acute ischemic stroke, and to develop safe and effective therapeutic strategies for improving stroke recovery.
Positions
Thanks for your interest. Currently there is no position available. Please email your CV to nirav.dhanesha@lsuhs.edu for future opportunities.
CONTACT THE LAB
Contact the Dhanesha Lab
LSU Health Shreveport
Department of Pathology and Translational Pathobiology
1501 Kings Highway
Shreveport, LA 71103
Nirav Dhanesha, PhD
Office: BRI F7-26 Lab: BRI F7-36
Phone: 318-675-7966 (Office)
Email: nirav.dhanesha@lsuhs.edu