NIH Grants Awarded from BBRC Pilot Projects

NIH/NIAMS R03 Award (2013 BBRC Pilot Project)

Title:    Quantitative Imaging at Subcellular Levels in Chondrocyte Mechanotransduction

PI:        Sungsoo Na, PhD, Biomedical Engineering

The long-term objective of the proposed project is to determine the effects of mechanical loading on osteoarthritic (OA) cartilage. Integrin-mediated Src/FAK signaling as well as Rho family GTPase such as RhoA is known to play an important role in cartilage maintenance and degradation.  Accumulating evidence suggests that in OA cartilage inflammatory cytokines such as interleukin 1b (IL1b) and tumor necrosis factor a (TNFa) elevate catabolic activities, whereas mechanical loading may act as a beneficial regulator depending on the loading magnitude. Despite previous studies, it remains unclear whether mechanical loading could attenuate cytokine-induced activation of Src/FAK and Rho GTPases that is linked to cartilage degradation.  Furthermore, little has been known about spatiotemporal dynamics of intracellular signaling of Src/FAK and GTPases at the sub-cellular level in response to cytokines and interstitial fluid flow.  In this proposal, fluorescence resonance energy transfer (FRET)-based biosensors together with a three-dimensional (3D) culture model will allow us to visualize the activities of signaling molecules at the sub-cellular level and evaluate the responses to fluid flow in the presence and absence of inflammatory cytokines.  We expect that this project will advance our understanding of the molecular mechanism of mechanotransduction involved in cartilage degradation, and it will contribute to treatment of degenerative joint diseases such as osteoarthritis.

NIH/NCI R21 Award (2013 BBRC Pilot Project)

Title:    Adaptable Hydrogel Platform to Study Pancreatic Cancer

PI:        Chien-Chi Lin, PhD, Biomedical Engineering

Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 80% of all forms of pancreatic cancer, the fourth leading cause of all cancer-related death. Understanding PDAC cell growth and motility is the key to developing effective drug therapeutics for treating PDAC. To date, most in vitro PDAC studies have been conducted on two dimensional (2D) tissue-culture plastic dishes (TCP) that are unnaturally stiff (E > 1 GPa). The ultrahigh stiffness of a 2D surface not only un-naturally polarizes the attached cells, but also causes the cells to behave differently due to abnormal mechano-sensing. The fate of PDAC cells are highly influenced by the stromal tissues (i.e., desmoplasia) in three-dimensional (3D) tumors. Desmoplasia communicates with pancreatic cancer cells to promote tumor progression and to hinder drug penetration and efficacy. Although a few studies have explored the utility of 3D matrices, such as Matrigel(R), for PDAC research, the commercially available matrices are mechanically weak and contain ill-defined and un- controllable biochemical components that may confound the experimental results. Our central hypothesis is that a synthetic tumor niche with dynamically and modularly adaptable properties can be used to elucidate the influence of extracellular matrix (ECM) cues on the growth, morphogenesis, and drug efficacy in PDAC cells. Toward this end, we will develop synthetic hydrogels that can be reversibly stiffened/softened via cytocompatible light exposure (365-430nm) in a range relevant to PDAC. We will also reveal the influence of these critical factors on drug resistance in PDAC. The information obtained from this study will open new therapeutic options for treating the lethal PDAC.