The Tie-2 receptor is highly and specifically expressed in endothelial cells. Its global constitutive activation in mature blood vessels is thought to mediate vascular quiescence. Sepsis is a common and morbid disease whose cardinal manifestations involve the vasculature. RATIONALE: Both the expression and activation of Tie-2 fall in experimental sepsis, creating a double-hit to its constitutive signalng. Stimulation of Tie-2 with recombinant Angiopoietin-1 (Angpt-1, its endogenous agonist ligand) or non-Angpt-1 peptide mimetics prevents multi-organ dysfunction and death in murine sepsis. Angpt-2, the context-dependent antagonist of Tie-2, is elevated in the circulation of septic individuals in proportion to the severity of disease, and early measurement of circulating Angpt-2 may predict adverse outcomes in patients with suspected infection. Despite these promising findings, little is understood about the direct local physiological contributions of impaired Tie-2 signaling and even less is known about the regulation of Tie-2 and its ligands in states of inflammation. HYPOTHESIS: We hypothesize that impaired Tie-2 signaling may contribute to the vascular leakage, vascular inflammation, and multi-organ dysfunction that contribute to death in sepsis.
AIMS : To test this, we propose 3 aims: (1) using tissue-specific tetracycline-inducible dominant-negative Tie-2 mice to study the acute and chronic consequences of locally impaired Tie-2 signaling; (2) applying cellular and rodent models of inflammation to identify mechanisms through which Tie-2 expression is suppressed; and (3) elucidating a mechanism of inflammatory Angpt-2 induction that may be attenuated by drugs currently being evaluated in critically ill populations. RESEARCH DESIGN: To execute these parallel aims, we have designed cellular mechanistic studies that will complement state-of-the-art mouse genetic models already validated in our laboratory. These tools will provide unprecedented insights into the biology of Tie-2 through gain- and loss-of-function experiments. We have assembled a team of experts in sepsis research, rodent physiology, mouse genetic models, and Tie-2 signaling to assist us.
Sepsis-the body's final response to severe infections-is a top-ten cause of adult death in the United States whose incidence is increasing and for which no targeted therapies are available. Our laboratory studies a molecular pathway, the Angiopoietin-Tie-2 axis that regulates the health of blood vessels throughout the body. The current proposal seeks to understand why Tie-2 signaling is switched off in sepsis, what the exact consequences are, and how we can restore the normal Tie-2 signal to benefit patients suffering from sepsis.
| Lynch, Matthew R; Tran, Mei T; Parikh, Samir M (2018) PGC1? in the kidney. Am J Physiol Renal Physiol 314:F1-F8 |
| Higgins, Sarah J; De Ceunynck, Karen; Kellum, John A et al. (2018) Tie2 protects the vasculature against thrombus formation in systemic inflammation. J Clin Invest 128:1471-1484 |
| De Ceunynck, Karen; Peters, Christian G; Jain, Abhishek et al. (2018) PAR1 agonists stimulate APC-like endothelial cytoprotection and confer resistance to thromboinflammatory injury. Proc Natl Acad Sci U S A 115:E982-E991 |
| Sangwung, Panjamaporn; Zhou, Guangjin; Nayak, Lalitha et al. (2017) KLF2 and KLF4 control endothelial identity and vascular integrity. JCI Insight 2:e91700 |
| Parikh, Samir M (2017) The Angiopoietin-Tie2 Signaling Axis in Systemic Inflammation. J Am Soc Nephrol 28:1973-1982 |
| Parikh, Samir M (2017) Angiopoietins and Tie2 in vascular inflammation. Curr Opin Hematol 24:432-438 |
| Retzlaff, Jennifer; Thamm, Kristina; Ghosh, Chandra C et al. (2017) Flunarizine suppresses endothelial Angiopoietin-2 in a calcium - dependent fashion in sepsis. Sci Rep 7:44113 |
| Druey, Kirk M; Parikh, Samir M (2017) Idiopathic systemic capillary leak syndrome (Clarkson disease). J Allergy Clin Immunol 140:663-670 |
| Ghosh, Chandra C; David, Sascha; Zhang, Ruyang et al. (2016) Gene control of tyrosine kinase TIE2 and vascular manifestations of infections. Proc Natl Acad Sci U S A 113:2472-7 |
| Parikh, Samir M (2016) Targeting Tie2 and the host vascular response in sepsis. Sci Transl Med 8:335fs9 |
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