IU Indianapolis ScholarWorks :: Browsing by Author "Allen, Matthew R."

Browsing by Author "Allen, Matthew R."

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11039 Indiana CTSI High-School STEM Summer Research Program: Future opportunities from a 2020 virtual program
(Cambridge University Press, 2021) Sanders, Elmer; Cruz, Leigh-Ann; Speidell, Emily; Schnabel, Rose; Balaji, Adhitya; Hogarth, Elise; Miller, Jade; Vaides, Sofia; Allen, Matthew R.; Medicine, School of Medicine
ABSTRACT IMPACT: The Indiana Clinical and Translational Sciences Institute K-12 STEM Outreach Program’s pivoted to a virtual program in summer 2020 which yielded novel approaches that could be retained in future years to extend the reach/impact of our pipeline program. OBJECTIVES/GOALS: Provide students with a meaningful and safe research experience during the COVID Pandemic. Develop new modules and approaches that could be delivered virtually. Engage students from communities that were not possible in previous years when in person meetings were required. METHODS/STUDY POPULATION: The program has historically supported over 100 high school students per year in a summer research internship for the last 5 years. Students are placed with academic research mentors in various Schools and Departments across the IUPUI campus, and also with industry laboratories. COVID-related restrictions required development of 100% virtual program. Key aspects of the virtual program included: cohort-based research mentor assignments with 1-4 mentees matched per research mentor, research projects that could be conducted virtually, heavy engagement of high-school teachers to facilitate the research experience with cohorts of mentees, a more rigorous virtual seminar series that included new modules such as COVID-specific programming and thus enhancing public education about COVID. RESULTS/ANTICIPATED RESULTS: The program served 130 students in summer 2020. We were able to recruit new faculty and industry mentors involved in data science research. As a result, we have now increased our mentor pool to serve more students in the future. Because student participation was virtual, we were able to accept students from further distances (up to 120 miles away) across the state. We were also able to accept local economically disadvantaged students that may have not been able to participate because of lack of reliable transportation. A positive unanticipated outcome was that mentees relationships with the mentors was established virtually thus increasing the potential for students to remain engaged in their research. DISCUSSION/SIGNIFICANCE OF FINDINGS: Adapting to a virtual platform provided research experience to high school students during a time when traditional approaches were not possible. Given some research experiences do not require in-person activities, this newly established model could be used moving forward to allow more statewide engagement in research experiences.
38460 Independent Investigator Incubator (I3) yields external funding within three years for the majority of junior faculty
(Cambridge University Press, 2021) Spence, John Paul; Santangelo, Christina R.; Buddenbaum, Jennifer L.; Carroll, Aaron E.; Allen, Matthew R.; Pediatrics, School of Medicine
ABSTRACT IMPACT: The Independent Investigator Incubator program provides 1:1 mentoring from ‘super-mentors’ to enhance junior faculty careers in research. OBJECTIVES/GOALS: In 2014, the Indiana University School of Medicine (IUSM) in collaboration with the Indiana CTSI established the Independent Investigator Incubator (I3) Program. The I3 Program is designed to provide 1:1 mentoring for new research faculty during the crucial early years of their careers. Our goal is to provide an overview of the I3 design and 5-year data. METHODS/STUDY POPULATION: The I3 Program employs a resource-sharing, centralized design that provides concentrated 1:1 mentorship from a senior faculty ‘super mentor’ as well as other resources, such as grant writing support. Unlike many mentorship programs, I3 mentors closely interact with the mentees within the School and are compensated for their efforts (5% full-time equivalency per mentee, max of 15%). The number of ‘super mentors’ has grown from 6 to 15 faculty over 5 years, and mentors typically serve 4 to 5 mentees. Mentee applications are accepted on a rolling enrollment basis. The I3 mentees represent a diverse group based on sex, ethnicity, terminal degree, academic track, and discipline. Mentors and mentees have annual reviews through the program. RESULTS/ANTICIPATED RESULTS: In five years, 110 mentees have enrolled in the I3 program. Upon entering, 53% had no external funding, 28% had internal funding, 12% had K-awards, 7% had R03/R21 awards. Over the first five years, 75% have received extramural funding. The median funding was $340,000 with nearly a third of mentees securing grants > 1 million in direct costs. For mentees who joined the program in its first three years (n=59), the average time to a notable extramural grant (defined as a NIH or foundation grant >$300K direct costs) was 2.2 years (median - 2.6 years). Nearly all mentees were satisfied with their mentor pairing based on the mentor’s ‘availability’ and ‘valuable feedback,’ and all mentees wanted the mentoring relationship to continue. DISCUSSION/SIGNIFICANCE OF FINDINGS: Since 2014, the I3 Program has had a positive impact on the careers of junior faculty at IUSM as determined by faculty satisfaction and funding metrics. Future focus areas will include developing criteria/models for graduating from the program to balance fiscal sustainability with mentee needs during their transition to mid-career.
6'-Methoxy Raloxifene-analog enhances mouse bone properties with reduced estrogen receptor binding
(Elsevier, 2020-01-17) Powell, Katherine M.; Brown, Alexa P.; Skaggs, Cayla G.; Pulliam, Alexis N.; Berman, Alycia G.; Deosthale, Padmini; Plotkin, Lilian I.; Allen, Matthew R.; Williams, David R.; Wallace, Joseph M.; Biomedical Engineering, School of Engineering and Technology
Raloxifene (RAL) is an FDA-approved drug used to treat osteoporosis in postmenopausal women. RAL suppresses bone loss primarily through its role as a selective estrogen receptor modulator (SERM). This hormonal estrogen therapy promotes unintended side effects, such as hot flashes and increased thrombosis risk, and prevents the drug from being used in some patient populations at-risk for fracture, including children with bone disorders. It has recently been demonstrated that RAL can have significant positive effects on overall bone mechanical properties by binding to collagen and increasing bone tissue hydration in a cell-independent manner. A Raloxifene-Analog (RAL-A) was synthesized by replacing the 6-hydroxyl substituent with 6-methoxy in effort to reduce the compound's binding affinity for estrogen receptors (ER) while maintaining its collagen-binding ability. It was hypothesized that RAL-A would improve the mechanical integrity of bone in a manner similar to RAL, but with reduced estrogen receptor binding. Molecular assessment showed that while RAL-A did reduce ER binding, downstream ER signaling was not completely abolished. In-vitro, RAL-A performed similarly to RAL and had an identical concentration threshold on osteocyte cell proliferation, differentiation, and function. To assess treatment effect in-vivo, wildtype (WT) and heterozygous (OIM+/-) female mice from the Osteogenesis Imperfecta (OI) murine model were treated with either RAL or RAL-A from 8 weeks to 16 weeks of age. There was an untreated control group for each genotype as well. Bone microarchitecture was assessed using microCT, and mechanical behavior was assessed using 3-point bending. Results indicate that both compounds produced analogous gains in tibial trabecular and cortical microarchitecture. While WT mechanical properties were not drastically altered with either treatment, OIM+/- mechanical properties were significantly enhanced, most notably, in post-yield properties including bone toughness. This proof-of-concept study shows promising results and warrants the exploration of additional analog iterations to further reduce ER binding and improve fracture resistance.
A Comprehensive Set of Ultrashort Echo Time Magnetic Resonance Imaging Biomarkers to Assess Cortical Bone Health: A Feasibility Study at Clinical Field Strength
(Elsevier, 2024) Jacobson, Andrea M.; Zhao, Xuandong; Sommer, Stefan; Sadik, Farhan; Warden, Stuart J.; Newman, Christopher; Siegmund, Thomas; Allen, Matthew R.; Surowiec, Rachel K.; Radiology and Imaging Sciences, School of Medicine
Introduction: Conventional bone imaging methods primarily use X-ray techniques to assess bone mineral density (BMD), focusing exclusively on the mineral phase. This approach lacks information about the organic phase and bone water content, resulting in an incomplete evaluation of bone health. Recent research highlights the potential of ultrashort echo time magnetic resonance imaging (UTE MRI) to measure cortical porosity and estimate BMD based on signal intensity. UTE MRI also provides insights into bone water distribution and matrix organization, enabling a comprehensive bone assessment with a single imaging technique. Our study aimed to establish quantifiable UTE MRI-based biomarkers at clinical field strength to estimate BMD and microarchitecture while quantifying bound water content and matrix organization. Methods: Femoral bones from 11 cadaveric specimens (n = 4 males 67-92 yrs of age, n = 7 females 70-95 yrs of age) underwent dual-echo UTE MRI (3.0 T, 0.45 mm resolution) with different echo times and high resolution peripheral quantitative computed tomography (HR-pQCT) imaging (60.7 μm voxel size). Following registration, a 4.5 mm HR-pQCT region of interest was divided into four quadrants and used across the multi-modal images. Statistical analysis involved Pearson correlation between UTE MRI porosity index and a signal-intensity technique used to estimate BMD with corresponding HR-pQCT measures. UTE MRI was used to calculate T1 relaxation time and a novel bound water index (BWI), compared across subregions using repeated measures ANOVA. Results: The UTE MRI-derived porosity index and signal-intensity-based estimated BMD correlated with the HR-pQCT variables (porosity: r = 0.73, p = 0.006; BMD: r = 0.79, p = 0.002). However, these correlations varied in strength when we examined each of the four quadrants (subregions, r = 0.11-0.71). T1 relaxometry and the BWI exhibited variations across the four subregions, though these differences were not statistically significant. Notably, we observed a strong negative correlation between T1 relaxation time and the BWI (r = -0.87, p = 0.0006). Conclusion: UTE MRI shows promise for being an innocuous method for estimating cortical porosity and BMD parameters while also giving insight into bone hydration and matrix organization. This method offers the potential to equip clinicians with a more comprehensive array of imaging biomarkers to assess bone health without the need for invasive or ionizing procedures.
A moderate spinal contusion injury in rats alters bone turnover both below and above the level of injury with sex-based differences apparent in long-term recovery
(Elsevier, 2024-04-10) Metzger, Corinne E.; Moore, Robert C.; Pirkle, Alexander S.; Tak, Landon Y.; Rau, Josephina; Bryan, Jessica A.; Stefanov, Alexander; Allen, Matthew R.; Hook, Michelle A.; Anatomy, Cell Biology and Physiology, School of Medicine
Spinal cord injury (SCI) leads to significant sublesional bone loss and high fracture rates. While loss of mechanical loading plays a significant role in SCI-induced bone loss, animal studies have demonstrated mechanical loading alone does not fully account for loss of bone following SCI. Indeed, we have shown that bone loss occurs below the level of an incomplete moderate contusion SCI, despite the resumption of weight-bearing and stepping. As systemic factors could also impact bone after SCI, bone alterations may also be present in bone sites above the level of injury. To examine this, we assessed bone microarchitecture and bone turnover in the supralesional humerus in male and female rats at two different ages following a moderate contusion injury in both sub-chronic (30 days) and chronic (180 days) time points after injury. At the 30-day timepoint, we found that both young and adult male SCI rats had decrements in trabecular bone volume at the supralesional proximal humerus (PH), while female SCI rats were not different from age-matched shams. At the 180-day timepoint, there were no statistical differences between SCI and sham groups, irrespective of age or sex, at the supralesional proximal humerus. At the 30-day timepoint, all SCI rats had lower BFR and higher osteoclast-covered trabecular surfaces in the proximal humerus compared to age-matched sham groups generally matching the pattern of SCI-induced changes in bone turnover seen in the sublesional proximal tibia. However, at the 180-day timepoint, only male SCI rats had lower BFR at the supralesional proximal humerus while female SCI rats had higher or no different BFR than their age-matched counterparts. Overall, this preclinical study demonstrates that a moderate contusion SCI leads to alterations in bone turnover above the level of injury within 30-days of injury; however male SCI rats maintained lower BFR in the supralesional humerus into long-term recovery. These data further highlight that bone loss after SCI is not driven solely by disuse. Additionally, these data allude to potential systemic factors exerting influence on bone following SCI and highlight the need to consider treatments for SCI-induced bone loss that impact both sublesional and systemic factors.
A novel murine model of combined insulin-dependent diabetes and chronic kidney disease has greater skeletal detriments than either disease individually
(Elsevier, 2022-12) Damrath, John G.; Metzger, Corinne E.; Allen, Matthew R.; Wallace , Joseph M.; Anatomy, Cell Biology and Physiology, School of Medicine
Diabetes and chronic kidney disease (CKD) consistently rank among the top ten conditions in prevalence and mortality in the United States. Insulin-dependent diabetes (IDD) and CKD each increase the risk of skeletal fractures and fracture-related mortality. However, it remains unknown whether these conditions have interactive end-organ effects on the skeleton. We hypothesized that combining IDD and CKD in mice would cause structural and mechanical bone alterations that are more deleterious compared to the single disease states. Female C57BL6/J mice were divided into four groups: 1) N=12 Control (CTRL), 2) N=10 Streptozotocin-induced IDD (STZ), 3) N=10 Adenine diet-induced CKD (AD), and 4) N=9 Combination (STZ+AD). STZ administration resulted in significantly higher blood glucose, HbA1c (p<0.0001), and glucose intolerance (p<0.0001). AD resulted in higher blood urea nitrogen (p=0.0002) while AD, but not STZ+AD mice, had high serum parathyroid hormone (p<0.0001) and phosphorus (p=0.0005). STZ lowered bone turnover (p=0.001). Trabecular bone volume was lowered by STZ (p<0.0001) and increased by AD (p=0.003). Tissue mineral density was lowered by STZ (p<0.0001) and AD (p=0.02) in trabecular bone but only lowered by STZ in cortical bone (p=0.002). Cortical porosity of the proximal tibia was increased by AD, moment of inertia was lower in both disease groups, and most cortical properties were lower in all groups vs CTRL. Ultimate force, stiffness, toughness, and total displacement/strain were lowered by STZ and AD. Fracture toughness was lower by AD (p=0.003). Importantly, Cohen’s D indicated that STZ+AD most strongly lowered bone turnover and mechanical properties. Taken together, structural and material-level bone properties are altered by STZ and AD while their combination resulted in greater detriments, indicating that improving bone health in the combined disease state may require novel interventions.
Adenine-induced chronic kidney disease induces a similar skeletal phenotype in male and female C57BL/6 mice with more severe deficits in cortical bone properties of male mice
(PLOS, 2021-04-23) Metzger, Corinne E.; Swallow, Elizabeth A.; Stacy, Alexander J.; Allen, Matthew R.; Anatomy and Cell Biology, School of Medicine
Chronic kidney disease (CKD) causes bone loss, particularly in cortical bone, through formation of cortical pores which lead to skeletal fragility. Animal models of CKD have shown variability in the skeletal response to CKD between males and females suggesting sex may play a role in this variation. Our aim was to compare the impact of adenine-induced CKD on cortical parameters in skeletally mature male and female C57Bl/6 mice. After 10-weeks of adenine-induced CKD, both male and female adenine mice had high serum parathyroid hormone (PTH), high bone turnover, and cortical porosity compared to non-CKD controls. Both sexes had lower cortical thickness, but only male mice had lower cortical bone area. CKD imparted greater deficits in mechanical properties of male mice compared to female mice. These data demonstrate that both male and female mice develop high PTH/high bone turnover in response to adenine-induced CKD and that cortical bone phenotypes are slightly more severe in males, particularly in mechanical properties deficits.
Adverse effects of autoclaved diets on the progression of chronic kidney disease (CKD) and CKD-Mineral Bone Disorder in rats
(Karger, 2020) Biruete, Annabel; Srinivasan, Shruthi; O’Neill, Kalisha D.; Vorland, Colby J.; Hill Gallant, Kathleen M.; Cai, Weijing; Uribarri, Jaime; Johnston, Nancy; Allen, Matthew R.; Chen, Neal X.; Moe, Sharon M.; Medicine, School of Medicine
Background: Autoclaving rodent diets is common in laboratory animals, but autoclaving increases the formation of dietary advanced glycation end-products (AGE). We studied the effect of autoclaved (AC) diet alone or in combination with a diet high in bioavailable phosphorus on biochemistries of chronic kidney disease-mineral and bone disorder (CKD-MBD), intestinal gene expression, and oxidative stress. Methods: Male CKD rats (Cy/+) and normal littermates were fed 1 of 3 diets: AC 0.7% phosphorus grain-based diet for 28 weeks (AC); AC diet for 17 weeks followed by non-autoclaved (Non-AC) 0.7% phosphorus casein diet until 28 weeks (AC + Casein); or Non-AC diet for 16 weeks followed by a Non-AC purified diet until 30 weeks (Non-AC + Casein). Results: AC diets contained ~3× higher AGEs and levels varied depending on the location within the autoclave. Rats fed the AC and AC + Casein diets had higher total AGEs and oxidative stress, irrespective of kidney function. Kidney function was more severely compromised in CKD rats fed AC or AC + Casein compared to Non-AC + Casein. There was a disease-by-diet interaction for plasma phosphorus, parathyroid hormone, and c-terminal fibroblast growth factor-23, driven by high values in the CKD rats fed the AC + Casein diet. Compared to Non-AC + Casein, AC and AC + Casein-fed groups had increased expression of receptor of AGEs and intestinal NADPH oxidase dual oxidase-2, independent of kidney function. Conclusions: Autoclaving rodent diets impacts the progression of CKD and CKD-MBD, highlighting the critical importance of standardizing diets in experiments.
Adverse mandibular bone effects associated with kidney disease are only partially corrected with bisphosphonate and/or calcium treatment
(Karger, 2013) Allen, Matthew R.; Chen, Neal X.; Gattone II, Vincent H.; Moe, Sharon M.; Anatomy & Cell Biology, School of Medicine
BACKGROUND/AIMS: Patients with chronic kidney disease (CKD) have a high prevalence of periodontal disease that may predispose to tooth loss and inflammation. The goal of this study was to test the hypotheses that a genetic rat model of progressive CKD would exhibit altered oral bone properties and that treatment with either bisphosphonates or calcium could attenuate these adverse changes. METHODS: At 25 weeks of age, rats were treated with zoledronate (ZOL), calcium gluconate, or their combination for 5 or 10 weeks. Mandible bone properties were assessed using micro-computed tomography to determine bone volume (BV/TV) and cementum-enamel junction to alveolar crest distance (CEJ-AC). RESULTS: Untreated CKD animals had significantly lower BV/TV at both 30 (-5%) and 35 (-14%) weeks of age and higher CEJ-AC (+27 and 29%) compared to normal animals. CKD animals had a significantly higher parathyroid hormone (PTH) compared to normal animals, yet similar levels of C-reactive protein (CRP). ZOL treatment normalized BV/TV over the first 5 weeks but this benefit was lost by 10 weeks. Calcium treatment, alone or in combination with ZOL, was effective in normalizing BV/TV at both time points. Neither ZOL nor calcium was able to correct the higher CEJ-AC caused by CKD. Calcium, but not ZOL, significantly reduced serum PTH, while neither treatment affected CRP. CONCLUSIONS: (i) This progressive animal model of CKD shows a clear mandibular skeletal phenotype consistent with periodontitis, (ii) the periodontitis is not associated with systemic inflammation as measured by CRP, and (iii) reducing PTH has positive effects on the mandible phenotype.
Adverse mandibular bone effects associated with kidney disease are only partially corrected with bisphosphonate and/or calcium treatment
(Karger, 2013-10) Allen, Matthew R.; Chen, Neal X.; Gattone II, Vincent H.; Moe, Sharon M.
Background/Aims: Patients with chronic kidney disease (CKD) have high prevalence of periodontal disease that may predispose to tooth loss and inflammation. The goal of this study was to test the hypotheses that a genetic rat model of progressive CKD would exhibit altered oral bone properties and that treatment with either bisphosphonates or calcium could attenuate these adverse changes. Methods: At 25 weeks of age, rats were treated with zoledronate, calcium gluconate, or their combination for 5 or 10 weeks. Mandible bone properties were assessed using micro-computed tomography to determine bone volume (BV/TV) and cementenamel junction to alveolar crest distance (CEJ-AC). Results: Untreated CKD animals had significantly lower BV/TV at both 30 (-5%) and 35 (-14%) weeks of age and higher CEJ-AC (+27 and 29%) compared to normal animals. CKD animals had significantly higher PTH compared to normal animals yet similar levels of C-reactive protein. Zoledronate-treatment normalized BV/TV over the first 5 weeks but this benefit was lost by 10 weeks. Calcium treatment, alone or in combination with zoledronate, was effective in normalizing BV/TV at both time points. Neither zoledronate nor calcium was able to correct the higher CEJ-AC caused by CKD. Calcium, but not zoledronate, significantly reduced serum parathyroid hormone (PTH) while neither treatment affected C-reactive protein. Conclusions: 1) this progressive animal model of chronic kidney disease shows a clear mandibular skeletal phenotype consistent with periodontitis, 2) the periodontitis is not associated with systemic inflammation as measured by C-reactive protein, and 3) reducing PTH has positive effects on the mandible phenotype.

Browsing by Author "Allen, Matthew R."

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