Congratulations to our 2011 Pilot Project Awardees!
Deborah A. Hall, MD, PhD
Anne-Marie Malfait, MD, PhD
Nicole M. Russo, PhD
Kharma Foucher, MD, PhD
Tibor A. Rauch, PhD
Raghu N Natarajan PhD
Tricia Johnson, PhD
Title: Neurological, Endocrine, and Molecular Phenotypes of FMR1 Premutation Carrier Women
PI: Deborah A. Hall, MD, PhD, Assistant Professor, Department of Neurological Sciences
Abstract: This proposal describes a study that will characterize phenotypes of female FMR1 premutation carriers, who are frequently caregivers of other family members with fragile X-associated disorders. The first two specific aims are to determine the neurological, neuropsychiatric, and endocrine phenotypes of FMR1 premutation carrier women using examinations and laboratory testing by specialists in these areas. The third aim is to determine the relationship between these phenotypes and molecular gene effects. The research design is a case control study with 30 female FMR1 premutation carriers and 30 female non carriers. Each subject will have a neurological examination from a neurologist, including the FXTAS motor rating scale and total neuropathy score scale; followed by testing from a neuropsychologist focused on cognitive function and psychiatric symptoms. An endocrinologist will review records, examine each subject, and perform laboratory testing to determine the presence of thyroid, ovarian, adrenal, and pituitary dysfunction. Subjects will complete surveys regarding sleep and have a skin biopsy for fibroblast collection. Serum and skin samples will be used to determine activation ratios, FMRP levels, AGG interspersions, and ASFMR1 transcript levels. The study is to be completed within two years and will provide preliminary data for a larger multi-site phenotype-genotype study. There are 780,000 female FMR1 premutation carriers in the US. Rush University has one of the largest programs for these women in the world, with over 200 active female FMR1 premutation carriers in clinical and research programs. Fragile X-associated disorders are associated with significant morbidity and there have been no objective studies investigating neurological or endocrine disorders in female FMR1 premutation carriers, given the lower risk of FXTAS due to X-inactivation. It is imperative for health care providers to better serve this population of women who are commonly caring for their intellectually disabled children and parents with progressive neurodegenerative disease.
Title: A Role of Pace4 in Osteoarthritis Pain
PI: Anne-Marie Malfait, MD, PhD, Assistant Professor, Departments of Biochemistry & Internal Medicine, Section of Rheumatology
Abstract: Background and Rationale. The long-term goal of this project is to define the contribution of the proprotein convertase, PACE4 (paired amino acid converting enzyme 4), to peripheral and central mechanisms of chronic pain generation in osteoarthritis (OA). Our understanding of the origins and mechanisms of pain in OA remains poor. It is, however, becoming apparent that acute pain episodes are mechanistically different from the underlying chronic pain associated with OA. Cumulative data suggest that chronic pain in OA can be generated through local mechanisms in the joint, while central sensitization phenomena intensify the pain sensation and may even result in symptoms typically associated with neuropathic pain.
We recently found that a single nucleotide polymorphism in PCSK6, the gene that encodes PACE4, protects against pain in subjects with knee OA. In addition, we showed that Pcsk6 null mutant mice are resistant to acute pain in a battery of algesiometric assays, implying a functional role for PACE4 in pain generation. PACE4 is broadly expressed in peripheral and central nervous system tissues involved in nociception, including dorsal root ganglia (DRG), amygdalae and spinal cord, all of which have been implicated in persistent pain.
Objective. In this one-year proposal, we aim to test the central hypothesis that inhibition of PACE4 decreases pain in a murine model of OA. We will determine the effect of PACE4 inhibition on OA-related pain in the DMM (Destabilization of the Medial Meniscus) model in male C57BL/6 mice. DMM offers a protracted model of OA, slowly progressing over more than 16 weeks post surgery. This enables the study of mechanisms of pain generation early in the disease and also at later stages, when joint pathology is severe and is accompanied by chronic pain.
Proposed Studies: DMM surgery will be performed in the right knees of 10-week old wild type (WT) and Pcsk6 null C57BL/6 mice. Up to 16 weeks post-DMM, pain-dependent measures will be monitored, including primary and secondary allodynia as measures of central and peripheral sensitization; and weight bearing, gait analysis, and locomotor activity as measures of spontaneous pain. Associated joint degeneration will be determined by histopathology. In order to identify molecular pathways associated with pain generation in WT and Pcsk6 null mice after DMM surgery, differentially expressed genes in DRG innervating the knee (L3-L5), in spinal cord, and in amygdalae in WT and Pcsk6 null mice (naive and post-DMM) will be determined through microarray analysis and quantitative RT-PCR.
Expected outcomes: These experiments will answer the question of whether PACE4 is essential for chronic pain generation in the DMM model. Information on genes that are differentially expressed post DMM in WT versus Pcsk6 null mice will provide insight in pathways involved in chronic pain generation. Novel targets for inhibiting pain may be uncovered. Findings here will set the stage for an R01 submission, where we intend to study the function of PACE4 in depth, and explore its potential as an analgesic target through use of a potent and selective inhibitor.
Title: Usability and Likeability of the Virtual Environment for Social Information Processing with Children
PI: Nicole M. Russo, PhD, Assistant Professor, Departments of Pediatrics and Behavioral Sciences
CO-I: Clark McKown, PhD, Assistant Professor, Departments of Pediatrics and Behavioral Sciences
Abstract: For nearly a quarter century, social information processing (SIP) skills have been a topic of intensive study. SIP skills include the ability to solve complex, naturalistic social problems, and they are consistently associated with a child's social and academic success. Specifically, the better children can identify and define social problems, develop appropriate social goals, and generate, select, and execute solutions to those problems, the more successful children are in their peer relationships.
Current approaches for SIP assessment require a tester (researcher, educator, or clinician) to read a child a vignette about a social conflict, or have the child view a video vignette, and then the tester asks the child a series of questions. Such approaches require a high level of expertise to administer, are not standardized, and are time-consuming due to coding and scoring requirements which make them less attractive tools for school systems. Additionally, outcomes of these assessments are only moderately correlated with a child's behavior in real-world situations. Thus, although there is a well-articulated theoretical model for understanding SIP skills (Crick & Dodge, 1994, 1996), the development of a scientifically sound and usable SIP assessment tool that more closely approximates being in the midst of a challenging social situation is needed.
We are developing such a tool, the Virtual Environment for Social Information Processing (VESIP), which can be used to understand the SIP strengths and needs of individual children. The VESIP is an automated, interactive, and computer-delivered tool that utilizes advanced 3D game technology to immerse a child in social situations and assess real-time social decision-making. We have already developed an initial prototype and the objective of this pilot study is to test the usability and likeability of that prototype in typically-developing (TD) school-aged children and children who are diagnosed with autism spectrum disorders (ASD), a population of children defined by impairment in social interactions. Our first aim is to demonstrate that children with and without ASD can use the VESIP and prefer its interactive format. Our second aim is to use the results of the pilot study to guide development of additional scenarios for the VESIP, including making any necessary modifications to its format based on child feedback. Our third aim is to gather initial evidence that the VESIP is sensitive to hypothesized differences between TD children and children with ASD. Accomplishing these aims advances us a major step towards creating a significantly improved, more flexible, and automated platform for the assessment of children's SIP skills that has potential for advancing the scientific study and clinical assessment of SIP skills.
Title: Development and Validation of a Novel Biomechanical Marker of Hip Osteoarthritis
PI: Kharma Foucher, MD, PhD, Assistant of Professor, Department of Orthopedic Surgery
Abstract: Individuals have an estimated 25% lifetime risk of developing symptomatic hip osteoarthritis (OA), a degenerative joint disease that is partly biomechanical in origin. It is a generally accepted concept that habitual joint loading, which can be quantified using gait analysis, contributes to OA progression and possibly initiation; however a full understanding of the role of gait biomechanics in hip OA is still emerging. In the case of knee OA, there is a validated biomechanical biomarker of disease progression and severity - the peak external knee adduction moment during walking. The existence of such a marker has led to the development of a variety of biomechanically-based, potentially disease-modifying treatment options currently under investigation, as well as a non-invasive, non-imaging-based tool for monitoring the success of other interventions. Research and improved therapies for hip OA could be accelerated by such a biomechanical marker, but so far none exists. Our overall goal in this work is to establish a similar tool for the hip by developing and validating a biomechanical biomarker of hip OA that is both diagnostic (associated with disease severity) and prognostic (predictive of disease progression). In this study we will first develop a diagnostic hip OA biomechanical marker. To accomplish this we will use a novel statistical approach, not previously used in musculoskeletal research, to exploit the unique biomechanical characteristics of the hip (many muscles with complex lines of action and several functions at different times during the gait cycle). Specifically we will apply the statistical approaches that have been used to develop combinatorial genetic markers of disease to our large motion analysis database of subjects with and without hip OA, to develop a diagnostic hip OA biomechanical marker. To validate the marker we will recruit and evaluate a set of subjects with mild to moderate disease (thereby overcoming another hole in the literature - the fact that most studies have investigated only subjects with endstage disease). These data will be used to both validate the markers and will serve as baseline (pilot) data for future longitudinal studies (to validate the marker as a prognostic tool). Our overall hypothesis is that a combination of gait variables is an effective diagnostic and prognostic marker of radiographic hip OA. After completion of this study, we will have established a non-invasive diagnostic biomarker that does not rely on costly imaging, and collected baseline data for a subject cohort that can be followed longitudinally in the future to evaluate the marker's association with disease progression. This valuable research tool will open the doors to needed new screening, diagnostic, evaluation, and therapeutic modalities for hip OA.
Title: Epigenetic Therapy for Polyarthritis
PI: Tibor A. Rauch, PhD, Assistant Professor, Department of Orthopedic Surgery, Section of Molecular Medicine
Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease with unknown etiology. Although significant progress has been achieved in understanding the immunology and the genetics of the disease, the epigenetic aspects of RA development and therapy have not been addressed according to its relevance. Experiments with the PG-induced arthritis (PGIA), a murine model of RA, showed that characteristic epigenetic alterations do occur in lymphocytes and contribute to the development and progression of polyarthritis. With the application of specific chromatin modifying enzyme inhibitors we could significantly delay the onset of disease and attenuate its severity. We will continue and extend our epigenome-wide research focusing on the identification of additional arthritis-specific alterations, including DNA methylation and histone modifications. Preliminary experiments performed on human mononuclear cell samples revealed similar expression profile changes as it had been observed in arthritic mice. Finally, we will determine whether epigenetic changes are responsible for conferring methotrexate (MTX) resistance to certain patients, which is a frequent problem during RA medication.
Our coordinated efforts (clinical, epigenomic, and bioinformatical approaches) toward elucidating epigenome-wide changes in RA should contribute to greater insight into the disease etiology and promote clinical studies.
Title: Transition Syndrome: Biomechanical Contributions to Adjacent Segment Disc Disease
PI: Raghu N Natarajan PhD, Professor, Department of Orthopedic Surgery
Co-I: Gunnar BJ Andersson MD, PhD, Professor, Department of Orthopedic Surgery
Abstract: The overall goal of the proposed project is to better understand the biomechanical effects on the adjacent discs of disc degeneration. Disc degeneration is frequently considered a reason why subsequent degeneration develops at mobile segments above or below the degenerated segment(s). This is clinically referred to as adjacent segments disc disease (ASDD) or transition syndrome in the case of a previous surgical treatment. The development of ASDD is problematic because it can necessitate further surgical intervention. Although the exact mechanism remains uncertain, altered disc biomechanical stresses, shifting of the center of rotation of the motion segment, transfer of motion from the affected disc to adjacent discs, increased intradiscal pressure at the adjacent segments, and change in facet loading pattern may all play a role in the development of ASDD. We believe that an improved understanding on how both disc degeneration and the surgical treatments of the degenerated disc can be achieved by the use of numerical techniques such as the Poro-elastic Finite Element Model (PFEM) that includes both poro-elastic properties of the disc as well as the physiological parameters such as osmotic pressure and strain dependent permeability. The PFEM will be used to quantify and hence allow comparison of how various variables associated with lumbar disc degeneration and its treatment contributes to ASDD.
To study this we will use a validated poro-elastic finite element model of the lumbar spine. We will model different stages of disc degeneration ranging from mild to severe and determine the change in disc kinematics, stresses, intradiscal pressure, facet loads and shift of the axis of rotation in segments adjacent to degenerated disc(s).
Near completion of the proposed pilot project, a grant application will be submitted to NIH (R01) and other agencies such as NSF on the transition syndrome due to different clinical approaches used in treating the degenerated lumbar discs. Effect on adjacent disc biomechanics due to different types of fusion and motion preservation systems normally used to treat patients with degenerated discs will be first determined using in-vitro experiments on cadaver specimens. The validated poro-elastic finite element model (PFEM) developed under the pilot project will then be modified to correspond to types of fusion, level fused and the number of levels fused in in-vitro experiments ("specimen specific"). The kinematics analyses from the cadaver specimens at each segment level will be compared with those from the corresponding modified "specimen specific" PFEM validating the model. The PFEM will then be used to study the effect of different variables such as severity of degenerated disc, number of levels that are degenerated, type of fusion, length of fusion and single or multi-level motion preservation system on ASDD. This study will provide, in a consistent fashion, a better understanding of the possible biomechanical contributions to ASDD. It will also provide clinically valuable information which can be used to quantitatively understand and prioritize the effects of different variables on minimizing the biomechanical effects on the adjacent segments.
Title: Economics Model of Human Milk as a Long-Term Prevention Strategy in Extremely Low Birth Weight Infants
PI: Tricia Johnson, PhD, Associate Professor, Department of Health Systems Management
Co-PIs: Aloka Patel, MD, Department of Pediatrics, Rush University; Paula Meier, DNSc, Department of Women, Children and Family Nursing and Department of Pediatrics, Rush University Medical Center; Janet L. Engstrom, PhD, Department of Women, Children and Family Nursing, Rush University, and Frontier Nursing University; Louis Fogg, PhD, College of Nursing; Kousiki Patra, MD, Department of Pediatrics, Rush University Medical Center
Abstract: Extremely low birth weight (ELBW; birth weight < 1000g) infants represent only 0.7% of all live births in the United States, but are susceptible to inflammation-based morbidities during the neonatal intensive care unit (NICU) hospitalization that lead to lifelong disability and high societal costs. These inflammation-based morbidities originate in the gastrointestinal tract shortly after birth and spread to fragile organs, including the brain, lung and eye, during their critical windows of development, thus affecting the structure and function of these organs. In addition to predisposing ELBW infants to a lifetime of poor neurodevelopmental outcome and chronic illnesses, these morbidities result in high societal costs. Human milk (HM) feeding during the NICU hospitalization represents a safe and effective short-term strategy for reducing the prevalence of these costly inflammation-based morbidities, and several studies indicate a dose-response relationship between high doses of HM and a reduction in the risk of specific morbidities, including late onset sepsis, necrotizing enterocolitis, chronic lung disease, periventricular leukomalacia and severe retinopathy of prematurity.
The objective of this research is to develop an economic model for evaluating the cost effectiveness of HM feedings received during the NICU hospitalization on societal costs (health care, educational and indirect costs due to lost caregiver productivity) through childhood (18 years) with data that we collect from a longitudinal cohort of 73 racially- and income- diverse ELBW infants. This study will merge existing NICU data from an NIH-funded study, Health Outcomes and Cost of Human Milk Feedings for Very Low Birth Weight Infants (NR010009), with neurodevelopmental outcome, chronic illness, and societal cost data collected from these same 73 ELBW infants when they reached 18-22 months corrected age. Then, societal cost data will be analyzed with respect to the dose and exposure period of HM feedings received by these infants during the NICU hospitalization to evaluate the long-term prevention impact of HM feedings for this population. These findings will have important health policy implications with respect to the prioritization of resources that enable HM feedings during the NICU hospitalization for fragile and costly ELBW infants.