2009 — 2012 |
Caudle, William Michael |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Vesicular Monoamine Transporter 2 as a Mediator of Pbde Neurotoxicity @ University of Washington
DESCRIPTION (provided by applicant) Concerns over the health risks associated with polybrominated diphenyl ethers (PBDEs) have been raised, especially given their ubiquitous environmental persistence and appreciable increases in their levels, both in the environment and human tissue. The penta-PBDE mixture, DE 71 has been demonstrated to inhibit the sequestration of dopamine by the vesicular monoamine transporter 2 (VMAT2) and generate oxidative stress. VMAT2 is a key mediator of cytosolic dopamine, regulating the accumulation and metabolism to neurotoxic reactive species. It has been well established that enhanced oxidative stress contributes to Parkinson's disease (PD) pathogenesis. Although the etiology of PD is unknown, epidemiological evidence has demonstrated a strong association between the environment and the development of PD. As DE 71 alters dopamine storage, this suggests that VMAT2 may be a putative target for DE 71 neurotoxicity. As our knowledge of the role that the environment plays in PD grows it will be important to gain a better understanding of the molecular mechanisms within the brain that are affected by environmental compounds. This proposal will examine the influence that disruption of dopamine handling by alteration of the VMAT2 has on DE 71-mediated degeneration of dopamine neurons. Furthermore, it will examine potential mechanism(s) by which DE 71 disrupts VMAT2. Completion of this project will be achieved through the candidate's involvement in a rigorous research environment where he will interact with his mentor and co-mentor, which will be critical to his acquisition of progressive experimental techniques and understanding of the daily responsibilities of a successful principle investigator. The comprehensive knowledge of toxicology and neuroscience, research techniques, laboratory management, and the commitment needed to succeed in academia that he will gain as a trainee will be immediately applied as he undertake the task of establishing his own laboratory. Not only will these skills facilitate a seemless transition to independence, they will also augment the candidate's ability to supervise a successful laboratory with the goal of elucidating the role of the environment in neurodegenerative disease.
|
1 |
2018 — 2021 |
Caudle, William Michael Chen, Jia Hao, Ke Marsit, Carmen Joseph |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Placental Functional Networks Linking Developmental Pesticide Exposure and Offspring Neurodevelopment
SUMMARY/ABSTRACT There continues to be an increase in the incidence and prevalence of neurobehavioral disorders. Considerable evidence has accumulated linking environmental toxicants, including pesticides, to these disorders and generally to detriments in neurobehavioral development. The placenta serves as a conduit of maternal signals and directs the developmental program through key roles it plays in nutrient transfer, metabolism, gas exchange, neuroendocrine signaling, growth hormone production, and immunologic control. These critical functions may be controlled by, as well as be reflected in, placenta genomics. Data from our group and others have demonstrated that environmental exposures including chemical and psychosocial factors can impact these placental functions reflected in variation in the molecular character of the placenta. Pyrethroid pesticides are a group of common insecticides and due to their persistence and widespread use are found with high prevalence throughout human populations. Increased pyrethroid exposures have been linked to a greater risk for attention deficit hyperactivity disorder (ADHD) in children as well as to cognitive defects. These insecticides can accumulate in and transfer through mammalian placentas and prenatal exposures have been linked to altered placental and neuronal functions including effects on the dopaminergic system. The scientific premise of this project is that the prenatal environment can disrupt critical functions of the placenta, reflected in placental gene networks, leading to alterations in communication of environmental signals between mother and fetus, and ultimately the development of postnatal health and disease. Thus, the placenta is the central organ for the developmental origins of health and diseases (DOHaD) paradigm. We specifically hypothesize that disruption of gene networks in the placenta by in utero exposures to common pyrethroids acts as a mediator of the impact leading to cognition and behavior deficit in the offspring. In a prospective pregnancy and birth cohort, with a primary focus on effects of prenatal pesticide exposure on newborn and early life neurobehavioral function, we will thoroughly interrogate the placenta genome to provide evidence for the molecular underpinnings of these effects. In parallel, we will utilize a highly characterized murine model of exposure to the one common pyrethroid, i.e. deltamethrin, to provide causal evidence of these placental genomic features as mediators of the environment?s effect on offspring neurodevelopment, and more importantly, to shed lights on relevance of placental gene networks to the programming in the brain, which will also be comprehensively interrogated. Our innovative, integrated modelling takes advantage of this bidirectional translational research approach and will provide an opportunity to define prevention or intervention strategies that can optimize the chances for successful pregnancy and health outcomes in children, as well as define novel biomarkers to classify risk at the earliest points in life so that interventions can be employed when they are most effective.
|
1 |