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FEATURED RESEARCH
ERI: Progressive Formation and Collapse Mechanisms of Sinkholes Caused by Defective Buried Pipes
This Engineering Research Initiation (ERI) award supports research that aims to understand why and how sinkholes form above defective buried pipes. Sinkholes induced by defective buried pipes have become a substantial threat to community safety, resulting in fatalities, damage to buildings and infrastructure, and economic loss. However, the collapse mechanism of sinkholes above buried pipes remains unclear, making prediction of sinkhole collapses difficult. In this project, the research team will identify the most susceptible soil and water flow conditions around defective pipes leading to sinkhole initiation and develop models to predict their growth. Currently, the US has more than one million miles of pipes nearing the end of their service lives that pose a sinkhole risk to their communities. This project will expand our understanding of formation and collapse mechanisms of such sinkholes to provide predictive capabilities. The research will also be complemented by establishing a responsive and flexible educational and outreach program based on curriculum development and K-12 summer camps that can motivate young students to pursue their college education in STEM fields. The research goal of this project is to predict sinkholes caused by defective buried pipes based on understanding of progressive formation and collapse mechanisms. To achieve this goal, the objectives are to (i) identify critical hydrogeological parameters leading to initiation of soil internal erosion around defective pipes through soil erosion tests in the laboratory; (ii) model the time-dependent progressive evolution of sinkholes induced by defective buried pipes using a sinkhole simulator; and (iii) develop an analytical method to predict the collapse timing and size of sinkholes considering external loads based on time-dependent soil arching models. This project will test three hypotheses: (1) internal soil erosion around defective buried pipes initiates when the ratio of hole diameter to D85 (i.e., 85% percent fines) of soil infill surrounding the pipe reaches a threshold value related to the hydraulic gradient; (2) sinkholes in a submerged zone will be cone-shaped with an angle from the horizontal direction that equals to the surrounding soil friction angle; and 3) sinkholes above the submerged zone will be dome-shaped, and collapse of the dome will be exaggerated by external loads. This project will allow the PI to advance knowledge of the sinkhole formation and collapse around defective buried pipes and to lay a firm foundation for his long-term career focused on safety and sustainability of buried civil infrastructures. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
Preservation of brain NAD+ as a novel non-amyloid based therapeutic strategy for Alzheimer’s disease
Tragically, there is currently a lack of effective medicines to prevent, treat, or reverse AD, and the problem is growing exponentially as our population rapidly ages. A large part of the failure to develop effective medicines for patients with AD is due to the disproportionate amount of resources that have been devoted to pursuing putative therapeutic targets linked to the largely unsuccessful amyloid hypothesis of AD. Only very recently has the first anti-amyloid based therapy been conditionally approved, and many major medical centers are declining to offer this to patients due to serious concerns regarding its safety and efficacy. Thus, it is imperative that we discover and develop new and complementary therapeutic targets for AD. Aging is well known to be the greatest risk factor for AD, and it has been demonstrated that brain nicotinamide adenine dinucleotide (NAD+) levels decrease in people as they age, and even more so in AD. NAD+ is a critical cofactor and energy metabolite in brain health and function, and we hypothesize that preserving brain NAD+ will prevent, treat, and potentially even reverse AD-like pathology and behavioral deficits in a preclinical mouse model of AD, known as 5xFAD mice. Importantly, we have also shown that this mouse model of AD is characterized by significantly diminished levels of brain NAD+ as well, thereby modeling this important aspect of human AD. We are testing our hypothesis with a novel small molecule compound (P7C3-A20) that crosses the blood-brain barrier (BBB) and potently and selectively stimulates activity of nicotinamide adenine monophosphate ribosyltransferase (NAMPT). NAMPT is the rate limiting enzyme in NAD+ synthesis, and peripherally-administered P7C3-A20 elevates brain NAD+ levels under conditions of disease or injury that would otherwise deplete NAD+. The protective effect of P7C3-A20 to preserve NAD+ and thereby block nerve cell degeneration has been demonstrated in multiple preclinical models, including mouse models of TBI, Parkinson’s disease, and stroke, as well as a monkey model of hippocampal nerve cell death. Extended daily administration of P7C3-A20 upwards of a year has shown no toxicity or side effects in any animal system, including monkeys in which extensive pathological analysis across all organ systems was conducted after 9 months of daily oral ingestion. Three early pathophysiologic features of AD that are dependent on NAD+ availability in the brain are axonal degeneration, BBB deterioration, and excessively high death of young hippocampal neurons that arise from adult hippocampal neurogenesis. We propose that augmenting NAD+ levels in the AD brain will provide a novel means of preventing, treating, and potentially even reversing AD. We will thus test whether treatment with P7C3-A20 will be effective in early-disease (treatment from 2-6 months of age), mid-disease (treatment from 6-12 months of age), and late-disease (treatment from 12- 18 months of age) in both male and female 5xFAD mice. Protective effects in these domains will also be correlated with objective measure of cognitive and neuropsychiatric behavioral function, as well as other classical pathologic features of AD, including neuroinflammation, tau pathology, and amyloid plaque accumulation. We predict that P7C3-A20 will preserve brain NAD+ levels and protect axonal structure, BBB integrity, and hippocampal neurogenesis at each of these disease stages, which will be associated with generally improved cognitive and behavioral function, as well as reduced damage in the brain. If so, then our results will establish robust proof of principle for a novel approach to preventing, treating, and possibly reversing AD by preserving normal NAD+ levels in the brain. Importantly, our results could also establish a basis for future clinical trials with a compound currently in drug development (P7C3-A20), together with a plasma biomarker of brain nerve cell degeneration (acetylated-tau) that we have previously established in both mice and humans.
Development and Translation of an Intracranial Auditory Nerve Implant
ABSTRACT The proposed project will build and evaluate the safety and design needs of a new type of intracranial auditory prosthesis that targets the auditory nerve between the cochlea and the brainstem (auditory nerve implant, ANI) in order to substantially improve hearing performance over the current standard of care, the cochlear implant (CI). Current CIs provide crucial speech information to many recipients, but do not restore normal hearing, and are particularly challenged in noisy or complex acoustic environments. Despite concerted efforts over the past 25 years, little overall improvement in CI performance has been obtained, primarily due to the poor electrode- neural interface in which the CI electrodes are immersed in cochlear fluids and separated from the auditory nerve by the cochlea's bony wall. The new approach will build upon encouraging data from animal studies, well-established human surgical techniques to access the auditory nerve, and high-density electrode and safe stimulation technologies currently available for human use in order to test the safety and efficacy of the ANI that enables direct contact between the electrodes and the auditory nerve. The ANI provides great promise of improved speech and music perception for its prospective recipients, by overcoming the challenge that has limited improvements in CIs for the past quarter century. The first aim is to design and build a full ANI system in accordance with regulatory requirements, including necessary reliability, safety, functional, biocompatibility, and sterilization testing for human use. The ANI system will be built by combining a well-established CI device in the auditory implant field with a novel electrode and cabling technology already being evaluated in human patients for other clinical applications. The second aim is to refine the ANI surgery in human cadaver experiments and acutely during other relevant in vivo operations to consistently position and anchor the electrode array and cabling into the target region. The third aim is to develop and validate critical psychophysical tests to properly evaluate the performance of the ANI during the pilot human study, which can then inform the design of a future clinical ANI device. The fourth aim is to seek regulatory approvals and set up the clinical trial infrastructure and monitoring entities. The fifth and final aim is to perform a pilot ANI study in up to three deaf patients to obtain safety, reliability and functionality data that can properly guide the design of a proceeding clinical device and a feasibility study.
Use of Novel Neuroimaging, Neuropsychological Methods, and Retrograde Memory Test to Detect Cognitive and Cerebral Disruption in Veterans with Mild Traumatic Brain Injury
Identification of neuroimaging-based markers sensitive to mild neurotrauma and neuropsychological markers of cognitive disruption is vital toward addressing the complex treatment needs of the large number of Veterans with histories of mild traumatic brain injury (mTBI). Although neuroimaging methods, particularly in the area of diffusion imaging (dMRI) continue to show promise, there are significant limitations in the traditional, diffusion tensor imaging (DTI) based approach in white matter (WM). Specifically, a high degree of heterogeneity of WM axon orientations and sampling from disparate tissue types within a voxel contribute to inaccurate estimates of tissue properties. These limitations, inherent in standard and widely used DTI methods, likely attenuate DTI sensitivity in the detection of mild forms of neurotrauma, particularly in key, complex WM regions shown to be most susceptible to mTBI. Likewise, cognitive research findings in mTBI have been mixed, with conflicting reports and unclear cognitive outcomes that likely cloud and confuse clinical decision-making. The heterogeneity of TBI, differences in injury characteristics, and a non-uniform cognitive profile among affected Veterans likely contribute to the decreased sensitivity and inconsistency shown across studies that have leveraged traditional means- based comparisons of traditional neuropsychological test scores. Indeed, indicators of mTBI often fail to align with imaging findings, cognitive reports, and functional outcomes reported by Veterans with histories of mTBI. In the proposed study, we will apply new tools and methods in order to more sensitively examine WM disruption and neuropsychological performance in 60 Veterans with mTBI and 60 Veterans without a history of TBI. Participants will complete a broad neurocognitive assessment, including a novel test of retrograde memory for news facts, and will undergo a dMRI scan. We propose that leveraging a novel neuroimaging approach—one that is robust to the limitations inherent in standard DTI protocols—will enable investigation of WM proximal to the sulcal depths where all-cause mTBI is thought to inflict the greatest damage given shearing effects at the gray matter-white matter border. We will use dMRI acquisition and analysis methods which combine single and double pulsed field gradient dMRI acquisitions via a novel technique called Joint Estimation Diffusion Imaging (JEDI) to integrate diffusion information at the voxel and subvoxel level. Equilibrium probability (EP), an anisotropy measure that is more robust to the complexities of crossing fibers and partial voluming effects, will be calculated using JEDI. In particular, we will interrogate EP of voxels residing in the sulci at the gray matter-white matter border in the frontal lobe. Simulation and histopathological studies show these regions to be most susceptible to acute and distal effects of mild neurotrauma given the shearing effects that are particularly damaging because of differing tissue densities of the gray-white border. Second, given our recent work showing the sensitivity of newer cognitive methods to detect neuropsychological deficits in mTBI and others with mild cognitive difficulties, we will investigate intra-individuation cognitive performance variability (IIV) as a marker of cognitive disruption in order to enhance brain-behavior associations in Veterans compared to traditional comparison of group means. We will also administer a new cognitive tool, the retrograde memory news events test (RM-NET) to determine if it is sensitive to the cognitive deficits and TBI characteristics in Veterans with chronic mTBI. Taken together, the proposed study presents an opportunity to investigate WM disruption within brain regions vulnerable to mTBI using a novel neuroimaging approach (JEDI), further assess a promising cognitive concept (IIV) and new cognitive test (RM-NET), which may improve the evaluation of clinical outcomes following mTBI, and examine potential associations between IIV and WM disruption in Veterans with mTBI. Such cutting-edge work can lay the foundation for enhanced understanding of the neurobiological underpinnings of mTBI and persisting postconcussive symptoms in Veterans with neurotrauma and may identify neuroimaging biomarkers and cognitive abilities useful to evaluate treatment response in future clinical trials.
Role of intestinal serotonin transporter in post traumatic stress disorder
Post traumatic stress disorder (PTSD) a devastating psychiatric disorder and one of the most difficult service- related disabilities in Veterans, nonetheless without a consistently effective therapy. The only FDA-approved drugs for the treatment of PTSD are the selective serotonin reuptake inhibitors (SSRIs); the response rate to these drugs, however, is relatively small requiring development of more specific and individually effective therapies. In this regard, the neurotransmitter and hormone, serotonin (5-HT) is well-recognized for its role in depression, anxiety, aggression, impulsivity, and suicidal behaviors, which are frequently found in PTSD patients. Serotonin transporter, (SERT; SLC6A4), regulates the extracellular availability of 5-HT, and is a common target for SSRIs. Linkage of the short allele of the SERT gene polymorphism has been implicated in increasing the vulnerability to develop PTSD and predicting poor treatment outcome. In this regard, SERT is abundantly expressed in the gut and its dysfunction has been shown to cause gut microbiota alterations; albeit its role in the predisposition or progression of PTSD is not fully understood. To gain insights into the role of gut- microbiota and SERT interactions in PTSD, we utilized our recently developed novel transgenic model with inducible overexpression of SERT restricted to intestinal epithelial cells (SOEIEC) that exhibits low fecal 5-HT levels (LC/MS). The mouse model of protracted social isolation (SI), was used as chronic stressor important to elicit PTSD-like increased aggression in resident intruder assays. Interestingly, males with SOEIEC under SI exhibited increase in aggression while females were resilient as compared to wild type counterparts. To understand the sex-dependent differences, we correlated the aggression with structure of gut microbial communities. The data demonstrated a strong negative association of aggression with genus Desulfovibrio (sulfate reducing bacteria) and positive associations with Bacteroidales, Gastranaerophilales, and genus- Anaerotruncus. How 5-HT pools in the gut impact upstream factors affecting gut microbiota and triggers downstream factors in the gut and brain leading to PTSD like behavior in a sex-dependent manner is not known. Thus, our proposed studies will use cell specific SOE (in IEC and in neurons) to further elucidate PTSD related fear conditioning responses and aggression behavior and elucidate the underlying molecular mechanisms across gut-brain axis (Aim 1). Additional studies utilizing SOE and SERT KO are needed to assess the causal role of SERT induced gut-microbiota changes in predisposing mice (M/F) to fear deficits/increased aggression (Aim 2). This will be achieved by fecal microbial transplant and assessing the functional role of gut microbial changes by integrating the PTSD-like behavior with downstream targets (single cell RNA seq) and selected metabolites along gut-brain axis. The outcome of the studies will provide novel insights into the role of intestinal SERT in PTSD predisposition and will pave the way for microbial based therapeutics for PTSD management.
