Dr. Westmark’s basic and translational science research laboratory studies pharmaceutical and dietary interventions for the treatment of fragile X syndrome, autism and Alzheimer’s disease with a focus on the synaptic function of amyloid beta protein precursor (APP) and amyloid-beta. She employs mouse models of neurological disorders and human survey data to correlate promising treatments with improved behavioral (seizure, cognitive, hyperactivity/sleep) and biomarker data.
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| 1. Defining a Proteomic Signature for Soy-Induced Metabolic Changes in Mice Project Description: Our long-term goal is to implement a dietary intervention (restriction of soy-based infant formula in vulnerable populations) to reduce the incidence of childhood autism and obesity. The overall objective of this grant application is to identify nutritional biomarkers that are correlated with the consumption of a soy protein and obesity. The central hypothesis driving this proposal is that specific metabolic and proteomic biomarkers that are responsive to high dietary consumption of soy protein can be identified. Our hypothesis developed from our FRAXA Research Foundation-funded work (2008-2010) to evaluate the efficacy of the metabotropic glutamate receptor 5 (mGluR5) antagonist fenobam in mice. During the course of this work, we incorporated fenobam into a purified ingredient diet (casein-protein based) to ensure reproducibility in the formulation. Surprisingly, we discovered that the placebo purified diet significantly reduced seizure incidence and weight gain in juvenile mice in comparison to mice maintained on a standard rodent chow (Purina 5015, soy-based). The human correlate of juvenile mice fed a single-source, soy-based rodent chow is infants fed soy-based formula. Subsequent medical record and survey analyses suggest that consumption of soy-based infant formula could be contributing to the autism and obesity epidemics. This project is a collaborative effort with Dr. Lingjun Li in the School of Pharmacy to identify and validate nutritional biomarkers associated with soy protein by mass spectrometry. Staff: Pamela Westmark, Brynne Boeck, Timothy Swietlik |
| 2. Toward an Understanding of the Role of Infant Diet in the Development of Epilepsy: Seizures occur in many neurological disorders and may underlie the development of cognitive impairment and autistic behaviors. Seizure susceptibility is likely a combination of genetic and environmental factors where the effects of an underlying genetic mutation are exacerbated by, for example, a dietary exposure. We have found strong associations between the consumption of soy-based diets (chow for mice and infant formula for babies) and increased seizure incidence. This Grace Grant application will enrich our understanding of epilepsy by investigating associations between infant diet and the prevalence and severity of seizures in Dravet syndrome (DS) through a retrospective survey study of families enrolled in the Dravet Syndrome Foundation caregiver support group. We will also test our hypotheses prospectively in a mouse model useful for the study of DS. This proposal has strong potential to discern differences in developmental outcomes as a function of postnatal diet and early-life seizures in an experimental model with a high incidence of epilepsy. Positive findings would promote consideration of infant formula choice as a dietary intervention to reduce disease severity in DS and other epilepsy-related disorders. Staff: Pamela Westmark, Brynne Boeck, Rachel Nissan |
| 3. Preclinical Testing of the Effects of Diet and FMRP on Gut and Brain Barrier Integrity in a Mouse Model of Fragile X: FXS is a developmental disability caused by a mutation in the FMR1 gene on the X-chromosome, which results in loss of expression of fragile X messenger ribonucleoprotein (FMRP). FMRP is a messenger RNA (mRNA) binding protein that plays pivotal roles in the transport, localization and expression of hundreds of mRNAs. FXS is characterized by low IQ, autistic-like behavior and seizures. A critical gap in medical care for persons with FXS is a viable, mechanistic-based therapy that translate between preclinical and clinical research. Recent literature indicates worse neurological and metabolic outcomes (seizures, autism, increased body weight) in mouse and/or human models of FXS as a function of diet. Thus, early-life exposures, such as diet, may exacerbate disease outcomes. This DOD Discovery Award application is innovative in proposing to test for an FMRP- and tight junction-mediated mechanism underlying gastrointestinal (GI) and brain barrier function in FXS model mice as well as testing for diet-induced effects on gut barrier integrity. The goal is to determine the effects of pro- and anti-convulsive diets, i.e., soy- and casein-based single-source diets, on gut barrier structure and function in wild type and Fmr1KO littermate mice. The rationale is that loss of FMRP contributes to leaky gut syndrome through a tight junction-mediated mechanism affected by diet and that leaky gut contributes to brain dysfunction. This research has potential to provide a novel therapeutic target, tight junctions, and repurposing of experimental Celiac disease drugs that targe tight junctions for the treatment of FXS. Staff: Pamela Westmark, Brynne Boeck |
| 4. Preclinical Testing of High Fat / Low Carb Diets in Fragile X MiceProject Description: The ketogenic diet is highly effective at attenuating seizures in refractory epilepsy, and accumulating evidence in the literature suggests that it may be beneficial in treating autism. To our knowledge, no one has studied ketogenic, Atkins or other high fat/low carbohydrate diets in any model of fragile X syndrome (FXS). We tested the effects of chronic ketogenic diet treatment on seizures, body weight, ketone and glucose levels, diurnal activity levels, learning and memory, and anxiety behaviors in Fmr1KO and littermate control mice as a function of age (Westmark et al, 2020). The ketogenic diet selectively attenuates seizures in male but not female Fmr1KO mice and differentially affects weight gain and diurnal activity levels dependent on Fmr1 genotype, sex and age. FRAXA recently supported testing less stringent high fat/low carbohydrate diets with the Specific Aims to screen dietary percent fat and carbohydrate content for efficacy in attenuating audiogenic-induced seizures (AGS) in Fmr1KO mice and testing high fat/low carbohydrate diets on circadian activity levels in Fmr1KO mice. We are also testing the effects of ketogenic diet on sleep EEG outcomes and correlations with activity levels. Staff: Pamela Westmark, Timothy Swietlik, Rachel Nissan, Brian Corsiga, Maya Nebbia, Erica Jennings, Andrew Thauwald |
| 5. Testing Novel Drugs in Fmr1KO Mice Project Description: Fragile X syndrome is a rare disorder characterized by intellectual disability and a high seizure rate. Our research examines pharmaceutical and dietary approaches that reduce seizures in fragile X syndrome. The audiogenic seizure testing we perform is a routine test to assess seizure threshold, but there are only a handful of academic laboratories that are skilled in the methodology. The testing is beneficial to the pharmaceutical industry because positive results promote repurposing of their drugs to treat rare disorders. The testing is beneficial to families with Fragile X in that results provide preclinical efficacy data for novel treatments and identify candidate compounds to move on to clinical trials. Recent collaborations have examined the efficacy of novel Merz and Angelini Pharma compounds in a mouse model of fragile X syndrome (Fmr1KO mice). Staff: Pamela Westmark |
| Consumption of Breast Milk Is Associated with Decreased Prevalence of Autism in Fragile X Syndrome Westmark CJ. Nutrients. 2021 May 24;13(6):1785. doi: 10.3390/nu13061785. See full publication information |
| Parental Reports on Early Autism Behaviors in Their Children with Fragile X Syndrome as a Function of Infant Feeding Westmark CJ. Nutrients. 2021 Aug 22;13(8):2888. doi: 10.3390/nu13082888. See full publication information |
| How autism and Alzheimer's disease are TrAPPed Lahiri DK, Maloney B, Wang R, Sokol DK, Rogers JT, Westmark CJ. Mol Psychiatry. 2021 Jan;26(1):26-29. doi: 10.1038/s41380-020-00928-8. Epub 2020 Nov 12. See full publication information |
| Diet in the Treatment of Epilepsy Westmark CJ. Nutrients. 2021 Mar 12;13(3):917. doi: 10.3390/nu13030917. See full publication information |
| A Simple, Reliable and Inexpensive Method to Individually Identify Neonate Mice Westmark PR, Gutierrez A, Westmark CJ. Lab Animal Sci Prof. 2021 Jan-Feb;9(1):46-48. See full publication information |
| FMRP Regulates the Nuclear Export of Adam9 and Psen1 mRNAs: Secondary Analysis of an N(6)-Methyladenosine Dataset Westmark CJ, Maloney B, Alisch RS, Sokol DK, Lahiri DK. Sci Rep. 2020 Jul 1;10(1):10781. doi: 10.1038/s41598-020-66394-y. See full publication information |
| Folic Acid Fortification and Neural Tube Defect Risk: Analysis of the Food Fortification Initiative Dataset Murphy ME, Westmark CJ. Nutrients. 2020 Jan 18;12(1):247. doi: 10.3390/nu12010247. See full publication information |
| Preclinical testing of the ketogenic diet in fragile X mice Westmark PR, Gutierrez A, Gholston AK, Wilmer TM, Westmark CJ. Neurochem Int. 2020 Mar;134:104687. doi: 10.1016/j.neuint.2020.104687. Epub 2020 Jan 17. See full publication information |
| Reply to "The Fallacy of Using Administrative Data in Assessing the Effectiveness of Food Fortification. Comment on: Folic Acid Fortification and Neural Tube Defect Risk: Analysis of the Food Fortification Initiative Dataset. Nutrients 2020, 12, 247 Westmark CJ, Murphy ME. Nutrients. 2020 May 8;12(5):1335. doi: 10.3390/nu12051335. See full publication information |
| Soy-Based Infant Formula is Associated with an Increased Prevalence of Comorbidities in Fragile X Syndrome Westmark CJ, Kniss C, Sampene E, Wang A, Milunovich A, Elver K, Hessl D, Talboy A, Picker J, Haas-Givler B, Esler A, Gropman AL, Uy R, Erickson C, Velinov M, Tartaglia N, Berry-Kravis EM. Nutrients. 2020 Oct 14;12(10):3136. doi: 10.3390/nu12103136. See full publication information |
| Defining a Proteomic Signature for Soy-Induced Metabolic Changes in Mice Sponsor: USDA, NATL INSTITUTE FOOD & AGRICULTURE Award: 2018-67001-28266 PI: WESTMARK, CARA J 7/15/2018 - 7/14/2024 |
| Testing of Their Novel Drugs in Fmr1KO Models(FXS) Sponsor: NEURODETECTIVE INTERNATIONAL Award: PI: WESTMARK, CARA J 11/1/2018 - 10/31/2021 |
| Preclinical Testing of High Fat / Low Carb Diets in Fragile X Mice and Cells Sponsor: FRAXA RESEARCH FOUNDATION Award: PI: WESTMARK, CARA J 5/1/2021 - 4/30/2022 |
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