Lung diseases, such as acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis, affect millions of Americans and account for a great number of deaths in this country each year. The pathology of all of these diseases is characterized by initial injury to the epithelium, an extensive inflammatory response, and cell death (apoptosis and necrosis) leading to the aberrant healing of the injury. The inflammatory responses associated with lung injury have been extensively studied and several models of lung injury have been established to study these responses. LPS administration, for example, induces a significant tumor necrosis factor alpha (TNFa) response that mimics the inflammatory responses of several lung diseases. Activation of the cytokine TNFa is a hallmark of lung injury. TNFa is a well-characterized cytokine that displays a broad spectrum of functions including lymphocyte activation and migration, cell proliferation, differentiation as well as apoptosis, but more often cell survival, and TNFa likely requires a co-factor for cell death.
My research focuses on elucidating the mechanism(s) of cell death and survival of primary alveolar epithelial cells and lung fibroblasts in response to the extracellular matrix associated signaling molecule, CCN1/Cyr61. CCN1/Cyr61 is an extracellular matrix (ECM)-associated signaling molecule that functions to promote cell adhesion, migration, survival and differentiation in the context of vascular development. Most recently we have shown that CCN1/Cyr61 can also modulate cell death in certain cells and can promote cell death in response to TNFa. In the context of the lung, I have found that CCN1/Cyr61 together with TNFa causes apoptosis of alveolar epithelial cells and lung fibroblasts. Because CCN1/Cyr61 has been shown to be induced in the lungs of patients with COPD and ARDS, I hypothesize that CCN1/Cyr61, together with inflammatory mediators such as TNFa causes cell death of primary lung cells in vivo, thus contributing to lung injury. I have also found that CCN1/Cyr61 functional knock-out mice have greatly reduced pulmonary inflammation at early times (<24 hrs) after LPS treatment, suggesting that CCN1/Cyr61, in addition to playing a role in apoptosis and cell survival, is likely to be involved in the initial inflammatory response as well. My research goals include determining a role for CCN1/Cyr61 in lung injury and inflammation and defining the mechanism by which CCN1/Cyr61 and TNFa cause cell death of lung cells in vivo. The ultimate goal of these studies is to gain a better understanding of the complex pathology of lung diseases such as COPD and ARDS so that better treatments for these lung diseases can be developed.

• Young JL, Zimmer WE, Dean DA. Smooth muscle-specific gene delivery in the vasculature based on restriction of DNA nuclear import. Exp Biol Med (Maywood). 2008 Jul; 233(7):840-8.
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• Chen CC, Young JL, Monzon RI, Chen N, Todorovic V, Lau LF. Cytotoxicity of TNFalpha is regulated by integrin-mediated matrix signaling. EMBO J. 2007 Mar 7; 26(5):1257-67.
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• Machado-Aranda D, Adir Y, Young JL, Briva A, Budinger GR, Yeldandi AV, Sznajder JI, Dean DA. Gene transfer of the Na+,K+-ATPase beta1 subunit using electroporation increases lung liquid clearance. Am J Respir Crit Care Med. 2005 Feb 1; 171(3):204-11.
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• Dean DA, Machado-Aranda D, Blair-Parks K, Yeldandi AV, Young JL. Electroporation as a method for high-level nonviral gene transfer to the lung. Gene Ther. 2003 Sep; 10(18):1608-15.
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• Young JL, Benoit JN, Dean DA. Effect of a DNA nuclear targeting sequence on gene transfer and expression of plasmids in the intact vasculature. Gene Ther. 2003 Aug; 10(17):1465-70.
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• Shirasawa Y, Rutland TJ, Young JL, Dean DA, Joseph BN. Modulation of protein kinase C (PKC)-mediated contraction and the possible role of PKC epsilon in rat mesenteric arteries. Front Biosci. 2003 May 1; 8:a133-8.
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• Young JL, Dean DA. Nonviral gene transfer strategies for the vasculature. Microcirculation. 2002 Jan; 9(1):35-49.
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• Martin JB, Young JL, Benoit JN, Dean DA. Gene transfer to intact mesenteric arteries by electroporation. J Vasc Res. 2000 Sep-Oct; 37(5):372-80.
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