It is clear that the tissue microenvironment plays a critical role in regulating inflammation and tissue destruction. Chronic inflammation and tissue fibrosis lead not only to increased tumover of the extracellular matrix but also to an increase in inflammatory cells and mediators. We have shown that fragments of the extracellular matrix component hyaluronan, produced at sites of tissue inflammation, playa central role in the activation of the innate immune system via TLR-2. We propose that the extracellular matrix is not only the target of inflammation, but in its low molecular weight form, plays a central role as an endogenous ligand inducing inflammation. The importance of low molecular weight hyaluronan (LMW HA) in lung injury is evident in CD44 receptor null mice thai die of overwhelming inflammation upon exposure to low dose bleomycin in the setting of massive accumulation of LMW HA. We have supportive data that LMW HA induces its Inflammatory signals via TLR-2 and TLR-2 null mice are protected from bleomycin injury. Furthermore, the absence of TLR- 2 reverses the increased mortality of bleomycin injured CD44 null mice. However, MyD88 null and TLR-4 null mice have increased bleomycin lung injury indicating the specificity of the LMW HA-TLR-2 pathway in bleomycin-induced lung injury. Thus, as LMW HA fragments appears to be important in inflammation, regulation of LMW HA Induced inflammatory responses may be important in effectively and specifically treating inflammatory disorders.. . We hypothesize that within the tissue microenvironment a critical mechanism for mediating inflammation is the LMW HA-TLR-2 activation of the innate immune system. To this end, we propose the following alms for the 2-year ARRA funding:
Specific Aim I will deflne the role of LMW HA-TLR-2 signaling in the bleomycin model of lung injury and Specific Aim II will define the role of bone marrow derived cells vs: resident lung cells in bleomycin lung injury using bone marrow transplantations in receptor deficient mice. By deflning and understanding the inflammatory properties of extracellular matrix components, we will better be able to identify specific pharmacologic targets as potential therapies. We believe that these studies will provide the pre-clinical basis for the use of specific agents in the treatment of inflammatory lung dis13ases such as idiopathic pulmonary fibrosis, chronic bronchitis and emphysema.
We believe that the revised version of this grant lends itself to fulfilling the mission of the NIH ARRA stimulus funding. First, by eliminating Aim III and paring down Aims I and II this proposal can now be completed within the 2-year funding period, without compromising its scientific integrity. Importantly, Aim II is independent of the outcome of Aim I. As such the two Aims can be performed simultaneously during the 2? year funding period. To facilitate this goal we have budgeted for hiring a new technician as well as a postdoctoral fellow. . As the purpose of the American Recovery and Reinvestment Act of 2009 Is to preserve and create Jobs, and for NIH awards to promote economic recovery by spurring advances In science and health, we believe our application fulfills those goals. In addition to the new research technician position requested, we have also budgeted for a new post-doctoral fellow position. In fact, 64% of the requested direct costs will go for salary support. With the additional personnel we will be beUer able to accomplish our aims. Additionally, a large portion of our supply budget is for animal purchasing and care, thus further supporting the jobs in our animal care facility. By defining and understanding the Inflammatory properties of extracellular matrix components, we will better be able to identify specific pharmacologic targets as potential therapies. We believe that these studies will provide the pre-clinical basis for the use of specific agents in the treatment of inflammatory lung diseases such as idiopathic pulmonary fibrosis, chronic bronchitis and emphysema. They will also spur the generation of preliminary data to apply for additional NIH and foundation grants. We are committed to complete this project's objectives in the 2 years allotted timeframe and acknowledge the rigorous (quarterly) reporting requirements.
| Black, Katharine E; Collins, Samuel L; Hagan, Robert S et al. (2013) Hyaluronan fragments induce IFN? via a novel TLR4-TRIF-TBK1-IRF3-dependent pathway. J Inflamm (Lond) 10:23 |
| Powell, Jonathan D; Pollizzi, Kristen N; Heikamp, Emily B et al. (2012) Regulation of immune responses by mTOR. Annu Rev Immunol 30:39-68 |
| Collins, Samuel L; Black, Katharine E; Chan-Li, Yee et al. (2011) Hyaluronan fragments promote inflammation by down-regulating the anti-inflammatory A2a receptor. Am J Respir Cell Mol Biol 45:675-83 |
| Scheibner, Kara A; Boodoo, Sada; Collins, Samuel et al. (2009) The adenosine a2a receptor inhibits matrix-induced inflammation in a novel fashion. Am J Respir Cell Mol Biol 40:251-9 |
