My 17 years of training has taken me through Aerospace, Biomedical Engineering and Chemistry departments. My expertise is in orthopaedic biomechanics and my research interests include understanding factors that influence the organization and assembly of the bone matrix. I have a successful publication record in the area, with 28 of my 30 publications dedicated to various aspects of bone and orthopaedic research. In addition, I was awarded an NIH F32 in 2008 to investigate nanoscale surface features of collagen in Osteogenesis Imperfecta. Although rooted in biology, I was trained as an engineer and approach studies from that perspective. In all papers where I was the first or corresponding author, the primary goal was to investigate bone through mechanical engineering or materials science lenses. These studies provide important material/mechanical data but often overlook the biological mechanisms behind the effects being measured, not because of a lack of interest, but a lack of understanding and training. The K25 mentored research program is an ideal mechanism for me. With a strong quantitative background I will be able to enhance my training in molecular biology theory and techniques to become an independent biomedical researcher with a translational focus. A common thread that passes through my previous experience is an interest in the roles collagen plays in bone health. My work focuses on conditions which alter specific known aspects of collagen in an attempt to understand how these factors impact whole bone structure and mechanical integrity. The goal of this training opportunity is to help me become a stronger independent investigator with the necessary background in molecular biology techniques I need to expand the scope of my research program to include both cellular/molecular and tissue/material responses to loading and disease. This career development plan is primarily based on laboratory training and experimentation carried out in my laboratory and those of Dr. Alex Robling (primary mentor), and Drs. Teresita Bellido and Lilian Plotkin (co-mentors) at the Indiana University School of Medicine (IUSM). Under the guidance of these experts in the molecular mechanisms governing disease and the response loading, I will learn how to properly design and execute mechanistic ex vivo and in vivo studies in bone using molecular biology approaches which will complement and bolster my strong engineering skill set. My training will be supplemented with didactic course work to strengthen my theoretical background in molecular biology, statistics, responsible conduct of research and grant writing. Along with my own 800 ft2 lab space, which is well equipped to conduct biomechanics and general cell culture research, I will also have access to all of the space and resources in my mentors' labs. The three mentors have 4500 ft2 of lab space on the 5th floor of the Van Nuys Medical Science Building at IUSM, a 5 minute walk from my lab and on the same campus. These labs have dedicated space for tissue culture and all aspects of molecular and cell biology. Core facilities in the MS building for microcomputed tomography, electron microscopy and histology are also available. Fully equipped animal facilities are present in both the PI's (2400 ft2) and the mentors' building (32,000 ft2). The combination of environment, space, equipment and collaborators ensures the availability of all resources needed for the successful completion of the proposed training plan. My long-term goal is to determine whether we can manipulate physical properties of collagen to increase fracture resistance in patients suffering from diseases related to bone fragility. The objective is to test whether mechanical loading can alter the sequential stages of collagen genesis, processing, maturity, and physical linkage, particularly in the context of skeletal disease, to produce healthier bone. The central hypothesis is that mechanical loading alters the expression and activity of collagen-modifying proteins and assembly/packing machinery that are affected in many matrix-related bone diseases. By demonstrating an approach that makes bone stronger through changes in collagen, beyond effects in mineral or architecture, a paradigm shift may be possible in the way the orthopaedic community approaches bone disease prevention and treatment. This research is relevant to the NIH's mission to apply fundamental knowledge about the nature of living systems to extending healthy human life and reducing the burdens of illness and disability. The central hypothesis will be tested by pursuing the following specific aims: 1) To define how mechanical stimulation alters collagen synthesis at the cellular-molecular level, 2) To ascertain the mechanisms governing the response to loading at the tissue-material level, 3) To determine how loading prevents or rescues diseased phenotypes.
In aim 1, key steps in collagen synthesis will be interrogated in loaded and non-loaded conditions in OI and BAPN-treated mesenchymal stem cells.
In aim 2, in vivo tibial loading will be used to alter collagen synthesis and assembly and increase fracture resistance in normal mice.
In aim 3, loading will be used to prevent or rescue diseased bone phenotypes. This work is significant because it will show that mechanical modulation of collagen is a practical method to prevent or treat disease-induced changes in bone quality and fracture resistance. The work is innovative because it will challenge the current mineral/mass/architecture-centered dogma for controlling fracture, which neglects the contribution of collagen. This research has clear relevance to public health as it wil deliver a new understanding of mechanically-induced adaptation in bone with broader implications of providing new ways to target bone disease through mechanical alterations to collagen.
The objective of this proposed is to demonstrate that mechanical loading can modify genetic and acquired disease phenotypes, not by correcting the defect itself but by impacting steps in synthesis to correct collagen quality and beneficially impact fracture resistance. The ultimate goal is to deliver a new understanding of mechanically-induced adaptation in bone and to provide new ways to target bone disease through mechanical alterations to collagen. The worldwide Bone and Joint Decade initiative has ended, but this research still has clear relevance to public health and is germane to the NIH's mission to apply fundamental knowledge about the nature of living systems to extending healthy human life and reducing the burdens of illness and disability.
