Nathan J. Alves

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https://hdl.handle.net/1805/17674

Safer Clot Digestion through Nanotechnology

Venous thromboembolism (VTE) is a blood clot disorder that encompasses two related conditions-pulmonary embolism (blood clots in lungs) and deep vein thrombosis (DVT). According to the Centers for Disease Control and Prevention, VTE affects 900,000 people each year in the United States. One treatment method for VTE is enzyme-based pharmaceutical agents that dissolve the clot. All available clot-dissolving enzymes rely on the activation of the patient's innate clot-digesting system. This nonspecific clot digestion, which results in uncontrolled clearance of both the clot of interest and beneficial clots throughout the body, leads to bleeding complications, including intracranial hemorrhage, in 5-10 percent of patients.

Dr. Nathan Alves, the first tenure-track PhD faculty member primarily appointed in the Department of Emergency Medicine, along with IU colleague Dr. Jeffrey Kline, founded Indiana Lysis Technologies LLC (ILT) to develop and commercialize safer clot-digesting therapeutics to better control clot digestion and reduce the risk of off-target bleeding. The interdisciplinary nature of Dr. Alves' work, which spans the basic sciences, medicine, and engineering, facilitated the development of a targeted nanoparticle enzyme delivery system to clear blood clots.

ILT placed third in the 2017 BioCrossroads New Venture Competition and won "Best Biotech Invention" in the 2018 Notre Dame McCloskey Business Plan Competition.

Dr. Alves' work in developing next generation nanoparticle-based clot dissolving pharmaceuticals is another example of how IUPUI faculty are TRANSLATING RESEARCH INTO PRACTICE.

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Browsing Nathan J. Alves by Author "Agarwal, Stuti"

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    HIV-Nef Protein Persists in the Lungs of Aviremic Patients with HIV and Induces Endothelial Cell Death
    (ATS, 2019-03) Chelvanambi, Sarvesh; Bogatcheva, Natalia V.; Bednorz, Mariola; Agarwal, Stuti; Maier, Bernhard; Alves, Nathan J.; Li, Wei; Syed, Farooq; Saber, Manal M.; Dahl, Noelle; Lu, Hongyan; Day, Richard B.; Smith, Patricia; Jolicoeur, Paul; Yu, Qigui; Dhillon, Navneet K.; Weissmann, Norbert; Twigg, Homer L., III; Clauss, Matthias; Medicine, School of Medicine
    It remains a mystery why HIV-associated end-organ pathologies persist in the era of combined antiretroviral therapy (ART). One possible mechanism is the continued production of HIV-encoded proteins in latently HIV-infected T cells and macrophages. The proapoptotic protein HIV-Nef persists in the blood of ART-treated patients within extracellular vesicles (EVs) and peripheral blood mononuclear cells. Here we demonstrate that HIV-Nef is present in cells and EVs isolated from BAL of patients on ART. We hypothesize that HIV-Nef persistence in the lung induces endothelial apoptosis leading to endothelial dysfunction and further pulmonary vascular pathologies. The presence of HIV-Nef in patients with HIV correlates with the surface expression of the proapoptotic endothelial-monocyte–activating polypeptide II (EMAPII), which was implicated in progression of pulmonary emphysema via mechanisms involving endothelial cell death. HIV-Nef protein induces EMAPII surface expression in human embryonic kidney 293T cells, T cells, and human and mouse lung endothelial cells. HIV-Nef packages itself into EVs and increases the amount of EVs secreted from Nef-expressing T cells and Nef-transfected human embryonic kidney 293T cells. EVs from BAL of HIV+ patients and Nef-transfected cells induce apoptosis in lung microvascular endothelial cells by upregulating EMAPII surface expression in a PAK2-dependent fashion. Transgenic expression of HIV-Nef in vascular endothelial–cadherin+ endothelial cells leads to lung rarefaction, characterized by reduced alveoli and overall increase in lung inspiratory capacity. These changes occur concomitantly with lung endothelial cell apoptosis. Together, these data suggest that HIV-Nef induces endothelial cell apoptosis via an EMAPII-dependent mechanism that is sufficient to cause pulmonary vascular pathologies even in the absence of inflammation.