Medicine and Health Sciences Commons^™

Investigation Of Oncogenic Ras And Endoplasmic Reticulum-Mitochondria Calcium Flux And Their Relationship In The Context Of Tumorigenesis, Emma Anderson

Senior Honors Theses

Intracellular calcium as a signaling molecule is a pervasive feature of cellular pathways, especially those that manage internal homeostasis and transitions through the cell cycle, so much so that regulated, responsive calcium flux between the endoplasmic reticulum (ER) and the mitochondria has been suggested to play a major role in cancer development. Another factor commonly implicated in tumorigenesis is RAS, an oncogene that controls signaling for many pathways that are also regulated by calcium. While both calcium and oncogenic RAS signaling are implicated in cancer development, possible links between them have yet to be determined. The identification of these links …

Interrogating Race And Place-Based Inequities In Hiv And Covid-19, Rohan Khazanchi

EMET Projects

Over the last four years, I have developed a research focus examining the intersections of race, place, and health. My M.D. Honors Thesis reflects a snapshot of these efforts. In this collection of brief research reports, I leverage area-based measures to investigate structural inequities in three contexts: the HIV epidemic in our hyperlocal community, the early stages of the COVID-19 pandemic, and clinical trials for novel COVID-19 therapeutics. I apply novel social epidemiologic tools to measure and explore disparate outcomes. And, in reflecting upon my findings, I discuss concrete implications for clinicians, researchers, and policymakers alike.

Chapter 1: Neighborhood-Level Deprivation …

Predictors Of Hyperkalemia And Outcomes Of Dyskalemia In Us Veterans With Advanced Chronic Kidney Disease Transitioning To Dialysis, Ankur Dashputre

Theses and Dissertations (ETD)

Background: The kidneys play a crucial role in maintaining homeostasis of serum potassium levels (K+). Patients with advanced chronic kidney disease (CKD) are at a higher risk of experiencing dyskalemia events (i.e. hyper- and hypokalemia; especially the former) and thus future adverse outcomes. Currently, there is a dearth of literature on prediction models for hyperkalemia and the effects of dyskalemia on outcomes such as incidence of ischemic stroke and short-term hospital/emergency room (ER) utilization in an advanced CKD population transitioning to dialysis. Objectives: Using a nationally representative sample of US veterans with advanced CKD transitioning to dialysis, in the pre-dialysis …

Prevalence And Predictors Of Missed Dysplasia On Index Barrett's Esophagus Diagnosing Endoscopy In A Veteran Population, Theresa H Nguyen, Aaron P Thrift, Rollin George, Daniel G Rosen, Hashem B El-Serag, Gyanprakash A Ketwaroo

Faculty, Staff and Students Publications

BACKGROUND & AIMS: Limitations of endoscopic sampling may result in missed dysplasia at the diagnosis of Barrett's esophagus (BE). However, the role of close follow-up endoscopy is unclear. The aim was to evaluate the proportion of patients diagnosed with "missed" dysplasia within 18 months of their index nondysplastic BE (NDBE) diagnosis.

METHODS: This was a retrospective analysis of a cohort of BE patients diagnosed during 1990-2019 at the Houston VA. Patients with BE on index esophagogastroduodenoscopy (EGD) were classified as NDBE, indefinite dysplasia, or dysplastic (low- or high-grade dysplasia) based on initial biopsies. We identified NDBE patients who had follow-up …

Comparison Of Endoscopic Ultrasound-Directed Transgastric Endoscopic Retrograde Cholangiopancreatography Outcomes Using Various Technical Approaches, Firas Bahdi, Rollin George, Kavea Paneerselvam, Dang Nguyen, Wasif M Abidi, Mohamed O Othman, Isaac Raijman

Faculty, Staff and Students Publications

Background and study aims  Roux-en-Y gastric bypass presents an anatomic challenge for patients needing ERCP. EUS-directed transgastric ERCP (EDGE) offers high clinical success but carries considerable risk of adverse events (AEs) with no standardized technical approach. In our study, we review the safety and efficacy of our various EDGE technical approaches.

Patients and methods  A retrospective single-center study of all patients who underwent EDGE procedures between February 2018 and November 2019. Primary outcomes included comparing the technical and clinical success, AEs, and lumen-apposing metal stent (LAMS) migration rates per access route (gastrogastric vs jejuno-gastric), number of procedure stages (single-stage vs …

“Pandemias Políticas: The Effects Of Political And Social Instability On Infectious Disease Epidemiology In Latin America"”, Sarah H. Noonan

Senior Theses

This paper seeks to analyze the relationship between political and social unrest and conflict and infectious disease epidemiology in Latin America. An analysis of published literature regarding epidemiological, biomedical, political, and historical content was conducted to highlight potential connections between infectious disease epidemics and sociopolitical conflict in the region. Specific analyses of Smallpox, Venezuelan Equine Encephalitis, Chagas disease, Cholera, Dengue, and COVID-19 were conducted, in an effort to uncover potential causations and context of epidemics of these conditions. Results of this analysis depict a necessity for further research into public health and disease control mechanisms during times of conflict and …

Zanubrutinib For Treatment-Naïve And Relapsed/Refractory Chronic Lymphocytic Leukaemia: Long-Term Follow-Up Of The Phase I/Ii Au-003 Study, Akash Mukherjee, Denái R Milton, Elias J Jabbour, Alison M Gulbis, Tapan Kadia, Nitin Jain, Celina Ledesma, Jan Burger, Alessandra Ferrajoli, William Wierda, L Jeffrey Medeiros, Hagop Kantarjian, Richard Champlin, Issa F Khouri

Faculty, Staff and Student Publications

We aimed to study the risks of graft-versus-host disease (GVHD), non-relapse mortality (NRM) and survival outcomes of allogeneic stem cell transplantation (alloSCT) in patients with chronic lymphocytic leukemia (n = 17), Richter's syndrome (n = 14), or lymphoma (n = 18) after small molecule inhibitors (SMIs). Patients had a median of 4 prior therapies, including ibrutinib (n = 46; 94%), venetoclax (n = 19; 39%), and idelalisib (n = 6; 12%). Twenty-one (43%) had >1 SMI. P53 mutation was detected in 58% of patients. The 3-year overall and progression-free survival rates were 68% and …

Myelodysplastic/Myeloproliferative Neoplasms-Unclassifiable With Isolated Isochromosome 17q Represents A Distinct Clinico-Biologic Subset: A Multi-Institutional Collaborative Study From The Bone Marrow Pathology Group, Rashmi Kanagal-Shamanna, Attilio Orazi, Robert P Hasserjian, Daniel A Arber, Kaaren Reichard, Eric D Hsi, Adam Bagg, Heesun Joyce Rogers, Julia Geyer, Faezeh Darbaniyan, Kim-Anh Do, Kyle M Devins, Olga Pozdnyakova, Tracy I George, Paola Dal Cin, Patricia T Greipp, Mark J Routbort, Keyur Patel, Guillermo Garcia-Manero, Srdan Verstovsek, L Jeffrey Medeiros, Sa A Wang, Carlos Bueso-Ramos

Faculty, Staff and Student Publications

Classification of myeloid neoplasms with isolated isochromosome i(17q) [17p deletion with inherent monoallelic TP53 loss plus 17q duplication] is controversial. Most cases fall within the WHO unclassifiable myelodysplastic/myeloproliferative neoplasms (MDS/MPN-U) category. The uniformly dismal outcomes warrant better understanding of this entity. We undertook a multi-institutional retrospective study of 92 adult MDS/MPN-U cases from eight institutions. Twenty-nine (32%) patients had isolated i(17q) [MDS/MPN-i(17q)]. Compared to MDS/MPN without i(17q), MDS/MPN-i(17q) patients were significantly younger, had lower platelet and absolute neutrophil counts, and higher frequency of splenomegaly and circulating blasts. MDS/MPN-i(17q) cases showed frequent bilobed neutrophils (75% vs. 23%; P = 0.03), hypolobated …

Development And Characterization Of Anti-Galectin-9 Antibodies That Protect T Cells From Galectin-9-Induced Cell Death, Riyao Yang, Linlin Sun, Ching-Fei Li, Yu-Han Wang, Weiya Xia, Boning Liu, Yu-Yi Chu, Laura Bover, Long Vien, Mien-Chie Hung

Faculty, Staff and Student Publications

Antibodies that target immune checkpoint proteins such as programmed cell death protein 1, programmed death ligand 1, and cytotoxic T-lymphocyte-associated antigen 4 in human cancers have achieved impressive clinical success; however, a significant proportion of patients fail to respond to these treatments. Galectin-9 (Gal-9), a β-galactoside-binding protein, has been shown to induce T-cell death and facilitate immunosuppression in the tumor microenvironment by binding to immunomodulatory receptors such as T-cell immunoglobulin and mucin domain-containing molecule 3 and the innate immune receptor dectin-1, suggesting that it may have potential as a target for cancer immunotherapy. Here, we report the development of two …

Virtual Meetings During Covid-19 Pandemic: Is It Time To Say Goodbye To Physical Meetings?, Maseeh Uz Zaman, Nosheen Fatima

Department of Radiology

Abstract are not provided by the author/publisher

Institute For Global Health And Development : Issue 3 - April - June 2022, Institute For Global Health And Development

IGHD Newsletters

• Research Highlights
• Reflections from IGHD’s Associate Faculty
• Key Publications
• Webinars and Dialogues
• Celebration
• Collaborate With U

Elucidating The Role Of O-Glcnacylation And Gsk3b In Alzheimer's Disease, Emily Valencia

Selected Honors Theses

Alzheimer’s disease (AD) is one of the most common types of neurodegenerative disease. There are currently no treatment methods for AD, but there are treatments for some of the symptoms. Aberrant levels of both O-GlcNAcylation and GSK3ß have been found in patients with AD. Studies have suggested that there is a relationship between the level of O-GlcNAcylation and the phosphorylation of GSK3ß. In order to discover new treatment methods, the phosphorylation of GSK3ß should be explored. This study uses a western blot analysis to quantify the ratio of p-GSK3ß:GSK3ß between the experimental group (higher levels of O-GlcNAcylation) and a control …

Survey Of Pediatric Critical Care Fellows On Postresuscitation Debriefing, Nicholas A Rossi, Mia Benavidez, Harold S Pine, Shiva Daram, Wasyl Szeremeta

Faculty, Staff and Student Publications

Choanal atresia is a rare congenital airway malformation that presents a unique surgical challenge for pediatric otolaryngologists. Here we report two classic cases of choanal atresia and examine the surgical approaches to this entity. The first case was a four-day-old female with a history of CHARGE syndrome and bilateral mixed membranous and bony choanal atresia confirmed by a CT scan. After undergoing transnasal endoscopic repair, choanal stents were placed for four weeks, and the patient was seen three months postoperatively and found to be doing well with no respiratory concerns. The second case involved a healthy three-year-old female presenting with …

Causal Associations Between Covid-19 And Atrial Fibrillation: A Bidirectional Mendelian Randomization Study, Xiaoyu Zhang, Biyan Wang, Tao Geng, Di Liu, Qiuyue Tian, Xiaoni Meng, Qiaoyun Zhang, Mengyang Jiang, Yiqiang Zhang, Manshu Song, Wei Wang, Youxin Wang, Baoguo Wang

Research outputs 2022 to 2026

Background and aims: Observational studies showed that coronavirus disease (2019) (COVID-19) attacks universally and its most menacing progression uniquely endangers the elderly with cardiovascular disease (CVD). The causal association between COVID-19 infection or its severity and susceptibility of atrial fibrillation (AF) remains unknown. Methods and results: The bidirectional causal relationship between COVID-19 (including COVID-19, hospitalized COVID-19 compared with not hospitalized COVID-19, hospitalized COVID-19 compared with the general population, and severe COVID-19) and AF are determined by using two-sample Mendelian randomization (MR) analysis. Genetically predicted severe COVID-19 was not significantly associated with the risk of AF [odds ratio (OR), 1.037; 95% …

Evaluating The Utility Of Knowledge-Based Planning For Clinical Trials Using The Trog 08.03 Post Prostatectomy Radiation Therapy Planning Data, Kirsten Van Gysen, Andrew Kneebone, Andrew Le, Kenny Wu, Annette Haworth, Regina Bromley, George Hruby, James O'Toole, Jeremy Booth, Chris Brown, Maria Pearse, Mark Sidhom, Kirsty Wiltshire, Colin Tang, Thomas Eade

Research outputs 2022 to 2026

Background and purpose: Poor quality radiotherapy can detrimentally affect outcomes in clinical trials. Our purpose was to explore the potential of knowledge-based planning (KBP) for quality assurance (QA) in clinical trials. Materials and methods: Using 30 in-house post-prostatectomy radiation treatment (PPRT) plans, an iterative KBP model was created according to the multicentre clinical trial protocol, delivering 64 Gy in 32 fractions. KBP was used to replan 137 plans. The KB (knowledge based) plans were evaluated for their ability to fulfil the trial constraints and were compared against their corresponding original treatment plans (OTP). A second analysis between only the 72 …

A Multi-Disciplinary Approach To Chronic Cough In Children, Shraddha S Mukerji, Naga Jaya Smitha Yenduri, Eric Chiou, Siby P Moonnumakal, Joshua R Bedwell

Faculty, Staff and Students Publications

OBJECTIVES: (1) To highlight the important causes of chronic and recurrent cough in children. (2) To discuss multidisciplinary approach to management of chronic/recurrent pediatric cough.

METHODS: Review of scholarly articles, guidelines, expert panels via PubMed and Google Scholar.

CONCLUSION: Chronic cough (CC) in children is mainly attributed to persistent bacterial bronchitis, asthma, nonspecific cough, and gastroesophageal reflux disease (GERD) symptoms. A multi-disciplinary approach is cost-effective and aids with earlier diagnosis and appropriate treatment. Congenital or acquired narrowing of the subglottis is the leading ENT cause for recurrent croup (RC) in children. Laryngeal cleft-type 1 is commonly seen in children with …

Emergency Airway Management In Covid-19 Patients And Risk To Healthcare Workers: A Low-Middle Income Country Data From The Intubate Covid Registry, Faisal Shamim, M Nazir, Naseem A. Sheikh, Asma Salam, Badar Afzal Khan

Department of Anaesthesia

No abstract provided.

Paratesticular Solitary Fibrous Tumour Mimicking Cellular Angiofibroma: An Unusual Morphology And Rare Site, Madiha Bilal Qureshi, Muhammad Usman, Qurratulain Chundriger, Nasir Uddin

Department of Pathology and Laboratory Medicine

Solitary fibrous tumour (SFT) is a ubiquitous benign mesenchymal tumour of fibroblastic origin, which occurs most often in middle-aged adults. It usually presents as lung mass originating from pleura, but extrapleural occurrence is also common. Tumour is characterised by hypo- and hyper-cellular areas of spindle-shaped cells, arranged in haphazard manner with dispersed staghorn-shaped vessels. Surgical excision is the curative treatment. SFTs of the primary testicular or paratesticular region are extremely rare, but they exhibit histologic findings similar to SFTs originating at other body sites. Here, we report the case of a paratesticular SFT in a 37-year male, who presented with …

Perturbed Hematopoiesis In Individuals With Germline Dnmt3a Overgrowth Tatton-Brown-Rahman Syndrome, Ayala Tovy, Carina Rosas, Amos S Gaikwad, Geraldo Medrano, Linda Zhang, Jaime M Reyes, Yung-Hsin Huang, Tastuhiko Arakawa, Kristen Kurtz, Shannon E Conneely, Anna G Guzman, Rogelio Aguilar, Anne Gao, Chun-Wei Chen, Jean J Kim, Melissa T Carter, Amaia Lasa-Aranzasti, Irene Valenzuela, Lionel Van Maldergem, Lorenzo Brunetti, M John Hicks, Andrea N Marcogliese, Margaret A Goodell, Rachel E Rau

Faculty, Staff and Students Publications

Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth disorder caused by germline heterozygous mutations in the DNA methyltransferase DNMT3A. DNMT3A is a critical regulator of hematopoietic stem cell (HSC) differentiation and somatic DNMT3A mutations are frequent in hematologic malignancies and clonal hematopoiesis. Yet, the impact of constitutive DNMT3A mutation on hematopoiesis in TBRS is undefined. In order to establish how constitutive mutation of DNMT3A impacts blood development in TBRS we gathered clinical data and analyzed blood parameters in 18 individuals with TBRS. We also determined the distribution of major peripheral blood cell lineages by flow cytometric analyses. Our analyses revealed non-anemic macrocytosis, …

Targeting Protein Degradation To Uncover Novel Oncoprotein Drivers Of Acute Leukemia, Fatemeh Keramatnia

Theses and Dissertations (ETD)

Acute Lymphoblastic Leukemia (ALL), the most common childhood cancer and the second most common acute leukemia in adults, arises from clonal expansion of undifferentiated lymphoid precursor cells in bone marrow. Despite the extensive knowledge on its cytogenetic and molecular biology, ALL treatment remains highly challenging especially after relapse. Conventional chemotherapy has shown significant improvement in overall survival rates of pediatric patients up to 90%, however, treatment failure due to ALL relapse occurs in 15-20% of the cases. On the other hand, adults and elderly patients with ALL are considered difficult to treat populations with the 5-year overall survival of 30–40%. …

Immunomodulatory Roles Of The Lysosomal Sialidase Neuraminidase 1, Leigh Ellen Fremuth

Theses and Dissertations (ETD)

Background Sialic acids are key sugar moieties located at the non-reducing terminals of glycan chains on glycoproteins and glycolipids. By virtue of their location, they influence the functions and biochemical properties of the macromolecules they are bound to. Removal of sialic acids in mammalian cells is carried out by four sialidases, which are differentially expressed and localized in distinct subcellular compartments. Neuraminidase 1 (NEU1), the most abundant and ubiquitous of the four sialidases, functions primarily in the acidic environment of the lysosomes, but can hydrolyze substrates at the plasma membrane, at least in certain cell types. The enzyme initiates the …

Exposure To Per- And Polyfluoroalkyl Substances And Markers Of Liver Injury: A Systematic Review And Meta-Analysis, Elizabeth Costello, Sarah Rock, Nikos Stratakis, Sandrah P Eckel, Douglas I Walker, Damaskini Valvi, Dora Cserbik, Todd Jenkins, Stavra A Xanthakos, Rohit Kohli, Stephanie Sisley, Vasilis Vasiliou, Michele A La Merrill, Hugo Rosen, David V Conti, Rob Mcconnell, Leda Chatzi

Faculty, Staff and Students Publications

BACKGROUND: Experimental evidence indicates that exposure to certain pollutants is associated with liver damage. Per- and polyfluoroalkyl substances (PFAS) are persistent synthetic chemicals widely used in industry and consumer products and bioaccumulate in food webs and human tissues, such as the liver.

OBJECTIVE: The objective of this study was to conduct a systematic review of the literature and meta-analysis evaluating PFAS exposure and evidence of liver injury from rodent and epidemiological studies.

METHODS: PubMed and Embase were searched for all studies from earliest available indexing year through 1 December 2021 using keywords corresponding to PFAS exposure and liver injury. For …

Association Between Self-Reported Body Mass Index And Active Life Expectancy In A Large Community-Dwelling Sample Of Older U.S. Adults, Haomiao Jia, Erica I. Lubetkin

Publications and Research

Background: Obesity may have a protective effect (greater survival) in older adults, a finding known as the "obesity paradox." This study examined the association between self-reported body mass index (BMI) and active life expectancy (ALE) among older U.S. adults.

Methods: Using the Medicare Health Outcomes Survey Cohort 15 (2012 baseline, 2014 follow-up), we estimated life expectancy and ALE by participants' baseline BMI and age using multi-state models. A participant was classified as in an active state if this person reported having no difficulty for any of these six activities of daily living (ADLs).

Results: Small differences in life expectancy were …

The Correlation Between Vaccine Hesitancy And Privilege: Exploring The Degree To Which Education And Income Foster Resistance To Vaccination Efforts, Sophie Goldenberg

Independent Study Project (ISP) Collection

Vaccine hesitancy is a public health issue of growing concern. Extensive pre-existing literature offers several explanations and conflicting viewpoints regarding reluctance toward vaccinations. However, minimal research has been done exploring the upstream social determinants driving vaccine hesitancy. Utilizing academic and gray literature and interviews with experts in the field, this study addresses this gap in knowledge with the research question: To what extent does privilege impact vaccine hesitancy and resistance? Vaccine hesitancy appears globally and is particularly concerning given the re-emergence of vaccine-preventable diseases (VPDs). Additionally, due to inconsistent causes, vaccine hesitancy is difficult to combat. In referencing the history …

Evaluating The Validity Of Restrictions On Blood Donation Eligibility For Men Who Have Sex With Men (Msm) In The United States, France, And Switzerland, Swathi Gorantla

Independent Study Project (ISP) Collection

For the first time in a decade, the number of new human immunodeficiency virus (HIV) diagnoses is higher for heterosexual people compared to gay and bisexual men (Florêncio, 2022). Additionally, in the United States, the American Red Cross has declared a national blood crisis due to the nationwide shortage of donated blood. During this crisis, charged with the new information on HIV diagnosis rates, many advocates for the Lesbian, Gay, Bisexual, Transgender, Queer (LGBTQ+) community question why discriminatory policy surrounding gay and bisexual men donating still exist around the world. These policies are changing worldwide – several European countries have …

Prognostic And Predictive Value Of Β-Blockers In The Eortc 1325/Keynote-054 Phase Iii Trial Of Pembrolizumab Versus Placebo In Resected High-Risk Stage Iii Melanoma, Oliver J. Kennedy, Michal Kicinski, Sara Valpione, Sara Gandini, Stefan Suciu, Christian U. Blank, Georgina V. Long, Victoria G. Atkinson, Stéphane Dalle, Andrew M. Haydon, Andrey Meshcheryakov, Adnan Khattak, Matteo S. Carlino, Shahneen Sandhu, James Larkin, Susana Puig, Paolo A. Ascierto, Piotr Rutkowski, Dirk Schadendorf, Rutger Koornstra, Leonel Hernandez-Aya, Anna M. Di Giacomo, Alfonsus J.M. Van Den Eertwegh, Jean Jacques Grob, Ralf Gutzmer, Rahima Jamal, Alexander C.J. Van Akkooi, Caroline Robert, Alexander M. M. Eggermont, Paul Lorigan, Mario Mandala

Research outputs 2022 to 2026

Background:

β-adrenergic receptors are upregulated in melanoma cells and contribute to an immunosuppressive, pro-tumorigenic microenvironment. This study investigated the prognostic and predictive value of β-adrenoreceptor blockade by β-blockers in the EORTC1325/KEYNOTE-054 randomised controlled trial.

Methods:

Patients with resected stage IIIA, IIIB or IIIC melanoma and regional lymphadenectomy received 200 mg of adjuvant pembrolizumab (n = 514) or placebo (n = 505) every three weeks for one year or until recurrence or unacceptable toxicity. At a median follow-up of 3 years, pembrolizumab prolonged recurrence-free survival (RFS) compared to placebo (hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.47–0.68). β-blocker use was …

Identifying The 'Vulnerable Plaque' In Asymptomatic Carotid Artery Disease Patients, Zia Ur Rehman

Department of Surgery Docs

No abstract provided.

Quantifying The Effect Of Monitor Wear Time And Monitor Type On The Estimate Of Sedentary Time In People With Copd: Systematic Review And Meta-Analysis, Fiona Coll, Vinicius Cavalheri, Daniel F. Gucciardi, Sheldon Wulff, Kylie Hill

Research outputs 2022 to 2026

In studies that have reported device-based measures of sedentary time (ST) in people with chronic obstructive pulmonary disease (COPD), we explored if the monitor type and monitor wear time moderated the estimate of this measure. Five electronic databases were searched in January 2021. Studies were included if >70% of participants had stable COPD, and measures of ST (min/day) were collected using wearable technology. Meta-regression was used to examine the influence of moderators on ST, monitor type, and wear time. The studies identified were a total of 1153, and 36 had usable data for meta-analyses. The overall pooled estimate of ST …

Survivorship Research For People With Metastatic Or Advanced Cancer: A Time For Action, Andrea L. Smith, Nicolas H. Hart, Michael Jefford, Raymond J. Chan

Research outputs 2022 to 2026

Over recent decades, survival outcomes for people diagnosed with cancer have changed dramatically, with approximately 20% improvement in five-year relative survival rates in high-income countries including the United States and Australia. Regardless of regions, there is a decrease in overall cancer mortality rate of about 1% per year. Likewise, the cancer disease trajectory has changed. The traditional linear cancer trajectory in which a patient moves from cancer diagnosis through to a binary outcome (cure or death)—is no longer applicable and does not adequately describe the complexity of experience for many people. Indeed, the availability of targeted therapies and immunotherapies has …

Intestinal Deletion Of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Promotes Expansion Of The Resident Stem Cell Compartment, Alexandria M Doerfler, Jun Han, Kelsey E Jarrett, Li Tang, Antrix Jain, Alexander Saltzman, Marco De Giorgi, Marcel Chuecos, Ayrea E Hurley, Ang Li, Pauline Morand, Claudia Ayala, David R Goodlett, Anna Malovannaya, James F Martin, Thomas Q De Aguiar Vallim, Noah Shroyer, William R Lagor

Faculty, Staff and Students Publications

BACKGROUND: The intestine occupies the critical interface between cholesterol absorption and excretion. Surprisingly little is known about the role of de novo cholesterol synthesis in this organ, and its relationship to whole body cholesterol homeostasis. Here, we investigate the physiological importance of this pathway through genetic deletion of the rate-limiting enzyme.

METHODS: Mice lacking 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) in intestinal villus and crypt epithelial cells were generated using a Villin-Cre transgene. Plasma lipids, intestinal morphology, mevalonate pathway metabolites, and gene expression were analyzed.

RESULTS: Mice with intestine-specific loss of Hmgcr were markedly smaller at birth, but gain …