Medical Genetics Commons^™

Systems Genetics And Systems Biology Analysis Of Paraquat Effects In Bxd Recombinant Inbred Mice, Carolina Del Valle Torres Rojas

Theses and Dissertations (ETD)

Paraquat (PQ) is a chemical herbicide that is used in many countries including the United States. It is also highly acutely toxic to humans and has been used as a means of suicide. As PQ is applied mainly in agricultural settings, it moves to soil and well water. Chronic low dose exposure via drinking water may have adverse effects on humans, including increased risk for sporadic Parkinson’s disease (sPD). The etiology of sPD is unclear and the most accepted hypothesis states it is the result of the interaction between environmental factors and genetic susceptibility. Increasing evidence led us to infer …

Dissecting Drivers Of Basal Immunity And Acute Responses To Viral Infection, Aisha Nadia Hegab Souquette

Theses and Dissertations (ETD)

Heterogeneity in the human immune system can lead to limited vaccine efficacy, poor response to therapeutics, increased susceptibility to immune mediated diseases, and differential outcome to infection. Studies to date have suggested a role for biological, environmental, and genetic factors in immune variation; however, they are often focused on a specific subset of the population (e.g. ancestral group, age range) which can exclude phenotypes unique to a diverse population and bias results. To address this gap, we have utilized samples from healthy or influenza virus infected subjects from 8 distinct populations in 5 countries to conduct an integrative analysis of …

Genetic Variation And Sex Mediate Differential Responses To ∆-9-Tetrahydrocannabinol Among Inbred Mice, Cory Parks

Theses and Dissertations (ETD)

The plant Cannabis sativa has been used by people for both recreational and medicinal use for thousands of years, but scientific investigation of the plant and its components didn’t begin until the early nineteen hundreds when Cannabis components known as phytocannabinoids were characterized and later isolated. In the 1970’s, ∆9-tetrahydrocannabinol (THC) was isolated and recognized as the major constituent responsible for the psychoactive and intoxicating effects associated with consumption of cannabis. This opened the door for intensive research in the field that lead to the discovery of the endogenous cannabinoid system and its associated receptors, effectors of signaling, and biosynthetic …

Validation And Application Of A Novel Target-Based Whole-Cell Screen To Identify Antifungal Compounds, Christian Alexander Dejarnette

Theses and Dissertations (ETD)

Traditional approaches to drug discovery are inefficient and have several key limitations that constrain our capacity to rapidly identify and develop novel experimental therapeutics. To address this, we have devised a second-generation target-based whole-cell screening assay based on the principles of competitive fitness, which can rapidly identify target-specific and physiologically-active compounds. Briefly, strains expressing high, intermediate, and low levels of a preselected target protein were constructed, tagged with spectrally distinct fluorescent proteins (FPs), and mixed together. The pooled strains were then grown in the presence of various small molecules, and the relative growth of each strain within the mixed culture …

Current Prospects And Outlook Of Crispr/Cas Technology In Clinical Therapy, James Piper

Theses and Graduate Projects

Gene editing capabilities have expanded enormously since researchers first demonstrated the robust, accurate, and efficient endonuclease activity of the CRISPR/Cas riboprotein enzyme. Since this gene editing technique was first described in 2013, the prospect of gene therapy as a viable clinical tool has improved immensely. CRISPR/Cas techniques and the methods by which they are delivered into cells, have evolved rapidly since the technology􏰿s inception, and successful, intentional genetic alterations of numerous mammalian cell lines have been reported. As a research tool, CRISPR/Cas9 has already proven itself indispensable in a brief period of time. While there are not numerous clinical trials …

Determining The Genetic Control Of Neural Tube Malformation Through Genetic Interactions With Idgf3, Elli N. Fox

Honors Projects

Genetic mutations disrupting human neural tube formation can lead to birth defects such as spina bifida and anencephaly. Defects can result in lack of neural tube closure in either the caudal (spina bifida) or cranial (anencephaly) regions. Little is known about the genes that cause these malformations. Researchers have been using the model organism Drosophila melanogaster in an attempt to determine genes responsible for neural tube malformations. Recently, an ortholog of human chitin-like protein, imaginal disc growth factor 3 (Idgf3), has been identified as important in the proper formation of Drosophila egg dorsal appendages. However, the molecular mechanism responsible for …

The Impact Of Genetic Counseling On Direct-To-Consumer And Patient-Initiated Testing, Jennifer Hull

KGI Theses and Dissertations

Direct-to-consumer (DTC) testing provides consumers access to genetic testing without involvement or advice from a genetics specialist. While the expansion of DTC testing has increased consumer access to genetic interpretations, these reports can often provide a false sense of security and rarely cover enough genetic information to make significant interpretations about disease risk. Patient-initiated testing involves consumers seeking out and ordering more comprehensive genetic testing on a cash pay basis. A patient’s self-reported medical and family history is reviewed by a clinician before the test is ordered. These tests are often similar to clinically ordered genetic tests, including large panels …

Integrating Geriatric Assessment And Genetic Profiling To Personalize Therapy Selection In Older Adults With Acute Myeloid, Vijaya R. Bhatt

Theses & Dissertations

Integrating geriatric assessment for patient profiling and genetic profiling of leukemic cells represents an innovative approach to personalize therapy selection in older adults with acute myeloid leukemia (AML). We report results of a pre-planned interim analysis of a pragmatic phase II trial that utilized this strategy to personalize therapy. Patients ≥60 years with a new diagnosis of AML underwent geriatric assessment prior to initiation of treatment. Geriatric assessment of physical function, cognitive function and comorbidity burden were used to determine fitness for chemotherapy. Patients with good or intermediate-risk AML received intensive chemotherapy such as anthracycline and cytarabine (7+3) if determined …

Genetic Counselors' Experiences With And Approaches To Discordant Genotypic And Phenotypic Sex Detected Via Non-Invasive Prenatal Testing, Emily Stiglich

Dissertations & Theses (Open Access)

As the use of non-invasive prenatal testing becomes more ubiquitous during pregnancy, genetic counselors (GCs) will see clients more frequently for discordant sex identification via non-invasive prenatal testing (NIPT-DSI). Thus, it is imperative to investigate what GCs consider important when counseling about NIPT-DSI and assess how GCs perceive their role in such cases. Prenatal and pediatric GCs were surveyed regarding previous experiences of NIPT-DSI, comfort levels of topics relating to NIPT-DSI, and perceived importance of potential discussion topics in a counseling session (n = 108). The survey consisted of two vignettes, presenting cases of NIPT-DSI identified prenatally in one …

Genetic Counselors' Approaches To Direct-To-Consumer Genetic Testing For Hereditary Breast Cancer, Sarah Burke

Dissertations & Theses (Open Access)

Given the increasing availability of health-related direct-to-consumer genetic testing (DTC-GT) and third-party interpretation (TPI) services, it is likely that genetic counselors (GCs) will continue to encounter consumers that require follow-up counseling for their results. The National Comprehensive Cancer Network recommends clinical-grade genetic testing to confirm commercial results; however, the type of testing that GCs select remains uncharacterized. Therefore, we aimed to describe the specific recommendations that cancer GCs make for confirmatory genetic testing in probands who have already obtained DTC-GT results or TPI data that reported a BRCA1/2 pathogenic variant. We recruited 80 GCs specializing in hereditary cancer and administered …

Frequency Of Copy Number Variants Involving The Sex Chromosomes In A Clinical Setting, Autumn Vara

Dissertations & Theses (Open Access)

Copy number variants (CNVs) are a common finding in the clinical setting and contribute to both genetic variation as well as disease. Recently, studies have described the accumulation of multiple CNVs as a disease modifying mechanism. While it has been characterized how additional CNVs may play a role in phenotype, in which ways and to what extent sex chromosomes are involved has not been fully described. We performed a secondary data analysis using the DECIPHER database on 2,273 de-identified individuals with 2 CNVs. CNVs were designated primary and secondary based on our criteria and characteristics of both CNV groups were …

Investigating Medical Examiners' Practices: Genetic Evaluation For Fatal Acute Aortic Dissection, Bradley Power

Dissertations & Theses (Open Access)

Acute thoracic aortic dissection (TAD) is a life-threatening event with a hereditary component. Currently, pathogenic variants in 11 genes associated with aortic aneurysm and dissection predispose to a heritable form of disease thereby conferring an increased risk for TAD. Genetic testing plays a pivotal role not only in diagnosis, but also in risk stratification for relatives and medical management to prevent premature death from dissection. Due to its high fatality rate, medical examiners and coroners (ME/Cs) may be the first to identify TAD cases and initiate genetic testing for the decedent and at-risk relatives. ME/Cs were surveyed using three clinical …

Identification Of Genetic And Antigenic Variation And Evolution Pattern Among Influenza A And B Viruses In Thailand, Nungruthai Suntronwong

Chulalongkorn University Theses and Dissertations (Chula ETD)

Seasonal influenza viruses commonly cause respiratory disease and have a considerable impact on public health threats which annually estimates 3 to 5 million cases of severe illness worldwide. The triggering of the seasonal influenza epidemic results from a complex interplay between viral, host and external factors such as climate. Although vaccination is an effective tool for influenza prevention and its complications, the composition of vaccine strain has been changed every year due to influenza constantly evolving. Here, we aim to examine the association between influenza activity and local climate factors, host immunity, genetic and antigenic variation and evolution pattern among …

Monitoring Pathological Gene Expression And Studying Endogenous Epigenetic Architecture By Crispr/Cas9-Based Tool Development Using Alpha-Synuclein As A Model, Levi Adams

Electronic Theses and Dissertations, 2020-

Until recently, complete understanding of the endogenous activity of pathologically relevant genes was out of reach and research was confined to in situ work, plasmid-based constructs and artificial model systems. The development and expansion of the CRISPR/Cas9 genome editing technique has enabled us to explore the molecular underpinnings of gene activation using the cell's own endogenous regulatory environment. In this work, we report on the development of a novel tool to monitor the endogenous activity of a causative gene in Parkinson's disease, a-synuclein. We use CRISPR/Cas9 to insert a highly sensitive engineered luciferase at the C-terminal of a-synuclein and assessed …

Combination Of Investigational Cell-Based Therapy And Deep Brain Stimulation To Alter The Progression Of Parkinson’S Disease, Nader El Seblani

Theses and Dissertations--Pharmacy

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and the motor symptoms are caused by progressive loss of midbrain dopamine neurons. There is no current treatment that can slow or reverse PD. Our current “DBS-Plus” clinical trial (NCT02369003) features the implantation in vivo of autologous Schwann cells (SCs) derived from a patient’s sural nerve into the substantia nigra pars compacta (SNpc) in combination with Deep Brain Stimulation (DBS) therapy for treating patients with advanced PD.

The central hypothesis of our research is that transdifferentiated SCs within conditioned nerve tissue will deliver pro-regenerative factors to enhance the survival of …

Nanopore-Based Metagenomic Comparison Of Airway Colonizers Between Cystic Fibrosis Patients And Healthy Individuals, Anita Samadabadi

Honors Undergraduate Theses

Cystic fibrosis (CF) is an autosomal recessive genetic disorder involving a mutation in the CF transmembrane conductance regulator protein (CFTR), which causes dysfunctional transport of chloride ions across cell membranes. CF affects multiple body systems and a few of its symptoms include chronic cough, difficulty breathing, obstructive airway disease, bacterial pulmonary infections, maldigestion, malabsorption, pancreatitis, and male infertility. Until recently, treatment options have been limited to alleviating symptoms, but a new classification of drugs, CFTR modulators, provide an opportunity to slow the progression of the disease and improve clinical outcomes. The effect of CFTR modulators may be attributed to the …

Genetic Diversity Of Merozoite Surface Protein 1 Gene Of Plasmodium Falciparum In Thailand, May Myat Thu

Chulalongkorn University Theses and Dissertations (Chula ETD)

In 2030, World health organization's target is to eliminate malaria at least in 35 countries. At present, Thailand is low risk of malaria so that, it has the potential to eliminate. About 10 years ago, malaria prevalence was high along the country border areas. To prevent the recurrence in those areas, evaluation of drug susceptibility of parasites and vaccine are important. Therefore, basic knowledge on genetic diversity in malaria parasite is needed. Merozoite surface protein 1(msp1), one of the vaccine candidate genes, is useful for monitoring genetic diversity of the parasite and the potential gene of vaccine. However, high diversity …

Clincial Translational Science Research Of The Functional Role Of Large Conductance Potassium Channels In Selective Destruction Of Triple Negative Breast Cancer Cells, Gina Sizemore

Graduate Theses, Dissertations, and Problem Reports

ABSTRACT

The preliminary background that puts this research into context is threefold; it is the aggressive nature of triple negative breast cancer (TNBC), the complexity surrounding its pathology, and the significant lack of targeted treatment for this disease. To clarify the focus of my research, I have concentrated on identifying a targeted treatment for TNBC. In the process, I have identified cycles of reciprocity between treatment, clinical diagnosis, staging, and pathology that will be addressed in smaller papers. However, the weight of this work is in the discovery of a novel target for triple negative breast cancer. The value of …

Obese Zucker Rats As A Reverse Translational Model Of Human Left Ventricular Hypertrophy, Mackenzie Shelby Newman

Graduate Theses, Dissertations, and Problem Reports

Heart failure is a lifelong disability that for over half of those affected leads to mortality within five years after initial diagnosis. Left ventricular hypertrophy (LVH) is one of the most reliable independent predictors of heart failure. Pathological LVH is irreversible, but early diagnosis is often missed due to its asymptomatic nature. Obese Zucker rats (OZR), which develop obesity due to dysfunctional leptin signaling, naturally exhibit a LVH that mimics the obese human condition. Animal models are necessary because human donor tissue is scarce. The central hypothesis is that genes and proteins that are differentially expressed during development of LVH, …