Clemson University

NIH Research Projects · FY 2025 · 2021-02

SUMMARY Common and rare genetic diseases affect a large fraction of the world’s population. Elucidating the mechanisms by which naturally occurring genetic variants affect disease risk requires multidisciplinary expertise in quantitative, population, molecular, cellular and developmental genetics; statistics, bioinformatics and computational biology; and functional genomics in cell culture and animal models. We propose a Center of Biomedical Research Excellence (COBRE) in Human Genetics that constitutes a unique partnership between the Clemson University Center for Human Genetics and the Greenwood Genetic Center. Research in the COBRE in Human Genetics will focus on understanding the genetic, genomic, and epigenetic mechanisms by which molecular genetic variation affects rare and common diseases. The COBRE in Human Genetics will support four research projects from junior investigators that tackle several of the outstanding challenges facing modern human genetics, including the roles of human long non-coding RNAs in risk for human disease, the effects of structural variation on disease phenotypes and gene regulation, development of animal models for rare diseases, and incorporating context-dependent effects into statistical models predicting complex trait phenotypes from large scale genetic variation data. Eight Pilot Projects led by junior investigators will contribute additional breadth and depth of research topics to the COBRE in Human Genetics. The Research Project Leaders will be mentored by established external NIH-funded researchers as well as the three PIs. The Research and Pilot Project Leaders will be supported by an Administrative Core that provides a wide range of professional development activities. The COBRE in Human Genetics will establish both Internal and External Advisory Committees and implement a comprehensive Evaluation Plan. The projects will be supported by a state-of-the-art Genomics and Bioinformatics Research Core that will benefit two other Clemson University COBREs as well as other faculty at Clemson University and the Greenwood Genetic Center. The COBRE in Human Genetics has strong institutional support, with commitments to hire additional faculty to expand the scope of the research activities during this period of support, and to provide graduate student research assistantships to support the research projects. The research performed by the Project Leaders of the COBRE in Human Genetics will provide new knowledge of the mechanisms by which molecular genetic variation affects variation in complex traits in health and disease, enhance the national reputation of Clemson University as a research and training center in human genetics, and set the stage for future development of institutional training grants and program projects. This COBRE will strengthen the biomedical research infrastructure of Clemson University and increase the number of NIH-funded scientists in the state of South Carolina.

NIH Research Projects · FY 2024 · 2020-09

Abstract Only 12.7% to 82.9% of the U.S. population receives recommended prevention services, and more specifically, between 70.7% to 91.9% of U.S. children aged 19-35 months receive recommended immunizations (Centers for Disease Control and Prevention, CDC). The utilization of clinical decision support (CDS) can help to increase these rates. Meta-analyses have shown that CDS, as a component of electronic health records (EHRs), is effective in increasing preventive care services. The rules for a CDS involve the knowledge needed to decide a CDS’s behavior in clinical tasks. Continuous rule maintenance is necessary to keep a CDS updated, useful, and at its full potential. Outdated rules can lead to missing alerts for preventive services or even to a patient’s death due to outdated drug-drug interaction alerts. Currently, there are no publicly accessible, reusable, generic, and machine-interpretable CDS rules for immunization schedules. Historically, CDS has been utilized successfully in large academic institutions. In the United States, however, small practices provide healthcare services to a majority of the population, with the volume of physician office visits at about 7.4 times that of hospital visits. In view of rapidly increasing EHR adoption rates in the United States, CDS usage rates have reached 68.5% to 100% in office-based primary care settings, indicating that CDS currently plays an important role in small practices. To be able to regularly update CDS rules is critical to maintaining a CDS. CDS rule management and maintenance have been recognized as challenging in large institutions. Thus, we anticipate that CDS rule management and maintenance will be an obstacle for smaller primary care practices, especially those without in-house IT support. Ontology is the enabling technology of the Semantic Web. Ontology has the potential to improve the interoperability, reusability, and sharability of ontology-based CDS rules, which will reduce duplicate efforts by multiple stakeholders. We also propose to enable primary care providers, especially in settings without in- house IT support, to manage and maintain CDS rules independently. The output of the investigation will be beneficial to small primary care practices in the long term. Our efforts will contribute to more consistent preventive services, including improved immunization recommendation rates for the large population served by these practices. We propose to (1) build and validate an upper-level CDS ontology; (2) develop portable, reusable, and machine-executable CDS rules based on ontology for CDC-recommended immunization schedules; (3) develop implementation scripts for CDS rules; (4) implement CDS rules and evaluate their reuse, use, and maintenance in simulated primary care settings, and (5) revise ontology, CDS rules, and implementation scripts. The long-term goal is to achieve interoperable EHR across platforms seamlessly by utilizing individuals’ immunization records. The experience gained from this proposed investigation will provide a critical foundation for our long-term goal and help to solve “curly braces problem” in the reuse of CDS rules.

NIH Research Projects · FY 2025 · 2018-09

SUMMARY The overall goal of the South Carolina COBRE for Translational Research Improving Musculoskeletal Health (SC-TRIMH) is to advance our understanding of musculoskeletal diseases and their management by enhancing and expanding the biomedical research capacity at Clemson University. Phase I SC-TRIMH successfully established and implemented the new scientific paradigm of Virtual Human Trials (VTH) for translational research. Virtual Human Trials consists of powerful computational modeling combined with quantitative functional validation and in vivo assessment to expedite the development of new therapeutics, interventions, and devices for musculoskeletal health. The overarching SC-TRIMH Phase II approach is to continue promoting outstanding multidisciplinary and collaborative research to improve patient care using this new paradigm. SC- TRIMH is a multidisciplinary and interactive center promoting translational research for musculoskeletal health which supports junior investigators and enhances their research competitiveness. The specific aims are to: 1) expand the critical mass of funded investigators conducting musculoskeletal research by implementing the concept of VHT for the development of new devices, interventions, and therapeutics for musculoskeletal disorders; 2) strengthen innovative scientific cores that support and advance musculoskeletal research to provide SC-TRIMH researchers with the best support to move their research forward to patient care; and 3) advance the ongoing development of an independent, sustainable, multidisciplinary thematic program by promoting the planning of program project and center grants at the institution level by building teams of PIs in niche areas, establishing a platform for technology transfer and commercialization through collaborations with Clemson University Research Foundation and the South Carolina Research Authority for academic startups, and develop a strategy for administrative infrastructure and financial recovery for SC-TRIMH resources. The Center is led by a leadership team with multidisciplinary expertise coalescing resources and disciplines from Clemson University School of Health Research (CUSHR) and its clinical partner, PRISMA Health System (PHS). The scientific cores include: 1) Multi-scale Computational Modeling Core providing cluster computing, bioengineering, bioinformatics, and systems biology expertise to model patient/specimen specific musculoskeletal system at body, tissue, and cellular levels for the development of novel technology; 2) Advanced Fabrication and Testing Core to generate, refine, and optimize the function and performance of technology using the advanced micro and macro fabrication technologies; and, 3) Preclinical Assessment Core to provide animal testing and human cadaver analysis to assess the in vivo function of novel devices, interventions, and therapeutics. These cores will support Phase II Research Project Leaders (RPLs) to advance musculoskeletal health and facilitate their competitiveness for national research awards. Extensive institutional support including flexible funds and three new tenure-track faculty positions will contribute to the Center's long-term success and viability.

NIH Research Projects · FY 2026 · 2017-09

SUMMARY Illegal use of cocaine and other drugs is a worldwide health problem. The National Institute on Drug Abuse estimates the total costs of drug abuse and addiction due to use of tobacco, alcohol and illegal drugs at $820 billion a year, making substance abuse the most costly public health problem in the nation. Illicit drug use alone accounts for $193 billion in health care, productivity loss, crime, incarceration, and drug enforcement. In humans, susceptibility to the effects of cocaine and other drugs has a strong genetic component, but little progress has been made in identifying the underlying variants and genes, in part due to difficulty in obtaining sufficiently large sample sizes because of criminalization of substance abuse; variation in drug exposure, including simultaneous exposure to multiple drugs, alcohol and nicotine; and comorbidity with other neuropsychiatric disorders. These problems can be mitigated using model organisms, such as Drosophila melanogaster. In addition to benefits of low rearing costs, small size and a short generation interval, Drosophila has a wealth of publically available genetic resources. Importantly, many effects of psychostimulants on people are replicated in flies. Approximately 67% of fly genes have human orthologs, and therefore insights gained from Drosophila have translational potential. During the past period of support, we have used the D. melanogaster Genetic Reference Panel of inbred wild-derived fly strains with fully sequenced genomes, and outbred advanced intercross populations (AIPs) derived from DGRP lines, to perform genome wide association (GWA) analyses of drug consumption behaviors and gene expression. These analyses showed that variants associated with drug consumption phenotypes were largely located in non-coding genomic regions, and presumably exert their phenotypic effects via modulation of gene regulation. We derived gene regulatory networks from naturally occurring genetic variation in gene expression and constructed an atlas of gene expression changes in the Drosophila brain following cocaine exposure at single cell resolution. The challenge now is to understand how variants act jointly to affect variation in drug preference, and to determine the underlying molecular networks using systems genetics analyses. Here, we propose to use 1200 new DGRP lines to map naturally occurring variants and genes associated with cocaine preference with greatly increased power and precision than our previous studies, perform a systems genetic analysis to infer causal regulatory networks associated with cocaine preference, and use germline gene editing to prove causality of the genetic associations with cocaine preference and gene regulatory networks. Information obtained from these studies can serve as a blueprint for subsequent translational studies in mammalian systems and human populations based on orthology and evolutionary conservation of fundamental biological processes, and expand the genetic framework associated with variation in human drug susceptibility beyond the narrow range of candidate genes examined to date.

NIH Research Projects · FY 2026 · 2017-04

Project Summary Aortic aneurysms (AA) are degenerative diseases characterized by dilation caused by arterial wall microarchitecture destruction. AAs are a life-threatening condition with the potential to lead to dissection, rupture, and even fatality. High blood pressure, atherosclerosis, and smoking increase the risk of AA initiation and rupture. Some inherited connective tissue disorders, such as Marfan, Loeys-Dietz, or Ehlers-Danlos syndromes, can also increase the risk for AA. Due to procedural risks, surgical intervention is only recommended for large aneurysms or those with a high rate of growth. However, several small aneurysms rupture while many larger ones never do. As many as 90% of detected AAAs are small and do not meet the surgical criteria; these patients are “watchfully waiting” without any treatment. Currently, no pharmacological approaches are available to stop AAA progression. We have developed a novel nanoparticle (NP) delivery system conjugated with a unique elastin antibody that targets only degraded vascular elastin, a hallmark of all aneurysms, named DESTINeD. We have discovered elastin stabilizing and regeneration potential of polyphenol-pentagalloyl glucose (PGG) when delivered with DESTINeD. We hypothesize that increasing the strength of the aneurysmal aorta by stabilizing residual elastin and collagen and regenerating lost elastin will prevent the expansion and rupture of AAs. In Specific Aim 1, we will use an abdominal aortic rupture mouse models (Angiotensin II infusion with either intraperitoneal injection of TGF-b neutralizing antibody or adding β Aminopropionitrile, BAPN in drinking water) to test if rupture can be prevented using DESTIENeD therapy and whether arterial homeostasis will be restored and inflammation reduced. In Specific Aim 2, we will test the hypothesis that degraded elastin-targeting PGG- loaded nanoparticles can prevent aneurysm rupture in a mouse model of Marfan Syndrome. Marfan syndrome is caused by mutation of the fibrillin-1 gene that causes dysfunctional elastin deposition in connective tissues, and many of these patients develop severe cardiovascular complications such as thoracic AAs. Fbn1R/R homozygote mice develop ubiquitous aortic elastin fragmentation, an inflammatory-fibroproliferative response, and inflammation-mediated elastolysis so that 99% die of aortic rupture between 2-6 months of age. Here we will test if our nanoparticle therapy can stabilize elastin and collagen and repair ECM and prevent aneurysmal rupture and death. As a preclinical proof for our therapy, a swine model of the abdominal AA will be used in Specific Aim 3 to test if DESTINeD nanoparticles, with a humanized elastin antibody, would arrest growth and reverse existing AAs. If successful, ours will be the first injectable therapy that can be translated to prevent aortic dilation and rupture.

NIH Research Projects · FY 2025 · 2012-03

Project Summary Temporomandibular disorders affect ~35 million people in the US, with 3-8 times more women affected than men. Approximately 30% of temporomandibular disorder patients experience mechanical dysfunction of the articular disc (an avascular tissue) in the temporomandibular joint (TMJ), a load-bearing joint during oral function. However, the etiology of the temporomandibular disc dysfunction/displacement (TMDD) sub-population is poorly understood, including why women are disproportionately affected. Logical TMDD candidate bio-indicators include craniofacial morphology, TMJ biomechanics, disc nutrient availability, and disc metabolism, each of which show varying degrees of sexual dimorphism. These factors interact such that subject-specific craniofacial morphology drives TMJ biomechanics, and biomechanics regulates TMJ disc nutrient availability and cellular metabolism/homeostasis. Study results from the preceding R01 proved that in pigs the avascular TMJ disc nutrient environment is heavily dependent upon mechanical strain-dependent nutrient diffusion, and the nutrient environment has a profound effect on disc cell proliferation and differentiation leading to tissue dysfunction. Therefore, TMJ biomechanical and mechanobiological differences between sexes driven by craniofacial morphology in humans may be critical. Our preliminary data have demonstrated sex-differences in human TMJ loading due to sexual dimorphisms in craniofacial morphology, plus we have identified a TMJ morphologic phenotype that may also explain sex-differences in TMDD occurrence. Therefore, it is now necessary to determine sex differences in the mechanical strain-dependent nutrient transport properties and nutrient level- dependent energy metabolism of the human TMJ disc and investigate the plausible associations of craniofacial morphology and TMJ biomechanics through the mechanobiological pathway on TMDD development and progression. The central hypothesis of the proposed study is that craniofacial morphologic differences between sexes, as well as between healthy controls and TMDD patients, drive the differences of TMJ biomechanics and disc mechanobiology which can be used to predict individuals at greatest risk for TMDD development and progression. The long-term objectives are to understand the mechanobiological etiology of temporomandibular disorders, to identify risk factors specific for TMDD development, and to define TMDD mechanobiological mechanisms of progression. Through the identification of potential morphologic, biomechanical, and biological risk factors for TMDD development and progression, this work has promising clinical translation and lays the foundation for future human studies. Specific outcomes of the proposed study include: determination of the mechanical strain dependency of the temporomandibular disc nutrient environment and its impact on cell viability and energy metabolism in human tissues, an enhanced understanding of how subject-specific morphology results in subject-specific differences in temporomandibular biomechanics, and identification of TMDD-specific mechanobiological bio-indicators.