Jason R. Richardson, PhD DABT - US grants

[unreadable] DESCRIPTION (provided by applicant): [unreadable] Both genetic and environmental factors play key roles in the pathological manifestation of Parkinson's Disease (PD). Epidemiological studies have identified pesticide exposure as a specific risk factor for PD. Our lab and others have shown that the commonly used pesticide, deltamethrin, alters the expression and function of the dopamine transporter in adult mice. The dopamine transporter is a key regulator of dopaminergic neurotransmission and a gateway for dopaminergic toxins, such as MPTP. Thus, alteration of its function or expression may increase the susceptibility of dopamine neurons to damage by neurotoxins such as MPTP and the neurotransmitter dopamine by increasing their uptake into dopamine neurons. We now provide evidence that gestational and lactational exposure to deltamethrin at levels lower than used in the adult studies leads to long-term up-regulation of the dopamine transporter. Therefore, the purpose of this study is to examine the effects of deltamethrin on the development of the nigrostriatal dopamine system and to determine if such exposures increase the susceptibility of these animals to the parkinsonism-inducing neurotoxin MPTP. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a chronic, degenerative neurological disorder that is estimated to affect at least 1 million individuals in the U.S. and ovr 10 million worldwide. PD is a complex disorder, and no single gene has been linked to a significant percentage of cases, suggesting that environmental factors or gene-environment interactions may contribute to the etiology or clinical manifestation. A polymorphism in the xenobiotic transporter Multidrug resistance protein 1 (MDR1, also known as P-glycoprotein) that reduces its function has been observed more frequently in PD patients who were exposed to pesticides. This finding raises the possibility that altered MDR1 function increases the risk for PD in people exposed to pesticides. Since MDR1 is critically important in expelling chemicals from the brain, we have hypothesized that MDR1 actively effluxes pesticides from the brain and genetic or acquired deficiency in this transporter may contribute to neurodegeneration. Our main research aim is to identify MDR1 as a primary efflux transporter responsible for removing pesticides, including the herbicide paraquat that has been linked to dopaminergic neurodgeneration, from the brain and protecting against neurodegeneration. This is significant because 1) MDR1 is prominently expressed in human brain capillary endothelial cells and other neuronal cells, 2) a polymorphism in MDR1 has been associated with increased risk of PD in patients exposed to pesticides, and 3) neuroinflammation, which is associated with multiple degenerative diseases including PD, has been found to down-regulate MDR1. Therefore, it is expected that these data will provide a better understanding of the genetic and inflammatory regulation of MDR1 as well as the potential role of MDR1 in the retention of pesticides in the brain, and will allow us to determine the mechanism of gene-environment interactions between MDR1, pesticides, and neurodegeneration.

DESCRIPTION (provided by applicant) The Joint Graduate Program in Toxicology (JGPT) is a combined effort of Rutgers, the State University of New Jersey and the Robert Wood Johnson Medical School, and is based in the Environmental and Occupational Health Sciences Institute (EOSHI). Founded in 1981, the JGPT has trained more than 140 doctoral students, postdoctoral fellows and physician-scientists. Graduates of the JGPT have forged distinguished careers in academic, industrial and governmental toxicology research. The NIEHS T32 training grant is the driving force of the JGPT. This competitive renewal application requests funding for years 26-30 to support 6 pre-doctoral students and 3 postdoctoral fellows, including a physician-scientist. The central mission of the JGPT is to provide talented students and postdoctoral trainees with rigorous training in contemporary mechanistic toxicology and in-depth expertise in their individual field of research. The training program is highly interdisciplinary, with students performing research rotations with scientists from varied scientific backgrounds. Specialized research tracks in biochemical toxicology, cell signaling and inflammation and neurotoxicology reflect thematic areas in which JGPT faculty members are recognized as leaders. All pre-doctoral trainees perform research rotations within the EOSHI Clinic to gain experience in patient-based environmental medicine. The training is supported by an exceptional research environment centered at EOHSI that includes state-of-the-art instrumentation and strong institutional support, and that synergizes with the NIEHS Center of Excellence in Toxicology, the Cancer Institute of New Jersey, the New Jersey Institute of Food, Nutrition and Disease, the Center for Advance Biotechnology and Medicine and other units involved in environmental health research. Trainees benefit from an outstanding seminar program and close interactions with the local pharmaceutical industry. Intensive efforts are expended to attract students of outstanding quality. The training program vigorously recruits students from under-represented groups. Relevance: The unifying goal of the JGPT and this training grant is to prepare trainees to excel in the competitive and rapidly evolving arena of environmental health sciences. Toxicology is a core discipline in understanding the impact of chemicals on human health. For the last 25 years, this training grant has enabled the JGPT to develop scholars who have become leaders in academic, industrial, and governmental toxicology. Public Health Relevance: The Joint Graduate Program in Toxicology (JGPT) is a training program designed to instruct doctoral students, postdoctoral fellows and physician-scientists in the mechanisms by which exposure to chemicals in the environment cause disease in people, and to devise methods to prevent or treat these diseases. Trainees receive extensive laboratory training in laboratory techniques and emerging scientific concepts. The goal of the program is to train toxicologists to address emerging environmental health issues.

Using well-characterized clinical cohorts, we recently reported that serum levels of DDE, the metabolite of the organochlorine pesticide DDT is significantly higher in the serum of Alzheimer Disease (AD) cases and is associated with increased risk of AD diagnosis. Further, individuals harboring a polymorphism in APOE and having high serum levels of DDE performed worse on a cognitive task than either those with just the polymorphism or high DDE levels. Finally, we identified that DDT and DDE increase levels of amyloid precursor protein (APP), suggesting a possible mechanism by which DDT exposure may contribute to ADBased on our initial findings, the goals of this project include: (1) identifying the mechanism by which DDT exposure increases APP levels; (2) determining the effect of APOE genetic status on the effects of DDT on A? accumulation and oligomerization; and (3) assessing the effects of DDT exposure on AD pathology and behavioral dysfunction in transgenic mouse models humanized for APOE polymorphisms. We will achieve these goals using a combination of cutting edge techniques including epigenetic analysis, patient-specific stem cells, and transgenic mice harboring human polymorphisms.

This application from Florida International University (FIU) and Emory University requests support for a four-year research conference series to address critical scientific issues associated with reducing Alzheimer's Disease and Related Dementia (ADRD) inequities among ethnic minorities in the United States. The conference series we propose rests on interdisciplinary research using a population disease framework, with specific attention to ethnic groups and sex differences in pathways to neurodegenerative diseases. Genetics and family/personal health histories are non-modifiable factors, and modifiable factors include a wide range of lifespan environmental exposures and lifestyle factors. The conference series focuses on increasing understanding about how genetic factors are operating in concert with environmental exposures, family and personal health histories, and lifestyle factors to produce interactions that enhance or mitigate risk of ADRD within and between ethnic groups, specifically among African Americans, Latinos, and non-Latino Whites. These critical issues remain largely overlooked and are fundamental for increasing knowledge for disease modification using precision medicine and for pharmacologic and non-pharmacologic intervention development in under-represented populations in AD clinical trials. The 4 related specific aims of the series are: 1. To understand how the current evidence examines specific genes, individually or in combination, are differentially distributed by ethnicity and sex, and are associated with higher risk or protection against LOAD between and among higher risk ethnic groups. 2. To describe how genetic risk may be modulated by factors such as epigenetics, age, sex, environmental exposures, lifestyle/diet, family and personal health histories, social, and demographic factors between and within ethnic groups and women at disproportionate risk for LOAD. 3. To examine current knowledge about how comorbidities such as vascular diseases, diabetes, and mental health moderate or mediate the increase risk of ADRD in these under-represented populations. 4. To explore underlying theory, new findings, and innovative observation, instrument development and calibration for respondent or patient assessment, and measurement/analytic strategies to improve our understanding of the gene x environment interactions influencing ADRD risk and how methods may be modified or adapted for use in specific research applications with higher risk minority populations and women.