1987 — 1989 |
Rodier, Patricia M |
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. |
Role of Hg Distribution Cns Teratogenicity of Mehg @ University of Rochester
Mechanistic studies of teratogens often require some information on the distribution of the toxic agent and its metabolites. A number of basic questions about methylmercury' mechanisms of action might be answered if its microscopic distribution where known, but every attempt to visualize the compound has met with serious criticisms that have left teratologists with no validated method for localization of this potent neurteratogen. New data demonstrate that methylmercury (along with all other forms of Hg) can be localized by the use of 203Hg with emulsion autoradiography (Rodier and Kates, 1986) and that inorganic Hg can be localized by the use of a silver sulphide technique (Magos et al., 1985). Thus, we propose a double labeling technique which will allow localization of the active organic form and will follow its conversion to the less active inorganic form. These will be examined in a variety of cell types and treatment conditions which are known or thought to differ in their response to MeHg. These include 1) mature vs developing cerebral cortex. 2) Male vs female neonatal cerebellar cortex 3) proliferation vs post mitotic cells 4) cells protected or not protected by the blood-brain barrier 5) cells exposed to MeHg directly vs those exposed systemically. Whether or not the distribution of organic and inorganic Hg is correlated with injury in the situations under study, the results will provide the first detailed descriptions of Hg distribution in the CNS - a necessary starting point for other studies.
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1990 — 1993 |
Rodier, Patricia M |
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. |
Neuroendocrine Effects of Prenatal Exposure to Alcohol @ University of Rochester
Alcohol is a teratogen known to cause extensive damage to the brain, yet its effects on the neuroendocrine control of growth and reproduction have not been investigated. The hypothesis that the hypothalamic-pituitary axis may be injured by prenatal exposure is supported only by evidence of postnatal growth deficiencies in human and animal FAS, and by a few reports of delays or changes in sexual maturation, but a vigorous test of the hypothesis is warranted, because endocrine deficiencies are treatable, unlike most of the symptoms of prenatal injury. Using a different teratogen, we have demonstrated changes in the hypothalamus and pituitary, and in the postnatal growth rate of rats exposed in utero. Based on these studies, and studies of the hypothalamic control of the reproductive system, we propose to compare offspring of rats exposed to chronic 35% ethanol-derived calories with isocaloric controls on the following measures: a) The number of growth hormone releasing factor (GRF) neurons, somatotropin release inhibiting factor (SRIF) neurons, and the number of luteinizing hormone releasing hormone (LHRH) neurons in the hypothalamus. The number and activity of these cells is related to the pituitary release of growth hormone, luteinizing hormone, and follicle stimulating hormone. b) The size and immunohistochemical composition of the anterior pituitary, where the somatotropic and gonadotrophic cells produce their hormones. c) The average circulating levels of growth hormone an luteinizing hormone, and the response of each to stimulation of the pituitary. d) The pattern of postnatal growth from birth to 60 days. e) The age of puberty, as judged by vaginal patency and estrous cyclicity in females, and by testis descent in males. f) The histological development of the male and female gonad at 4, 35, and 60 days. While these measures will not assay every way in which the systems could be deficient, they will evaluate the most likely symptoms and sources of endocrine disturbances, filling a crucial gap in the FAS literature, and, perhaps, suggesting clinical solutions to some features of the syndrome.
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1994 |
Rodier, Patricia M |
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. |
Neuroendocrine--Prenatal Exposure to Alcohol @ University of Rochester
Alcohol is a teratogen known to cause extensive damage to the brain, yet its effects on the neuroendocrine control of growth and reproduction have not been investigated. The hypothesis that the hypothalamic-pituitary axis may be injured by prenatal exposure is supported only by evidence of postnatal growth deficiencies in human and animal FAS, and by a few reports of delays or changes in sexual maturation, but a vigorous test of the hypothesis is warranted, because endocrine deficiencies are treatable, unlike most of the symptoms of prenatal injury. Using a different teratogen, we have demonstrated changes in the hypothalamus and pituitary, and in the postnatal growth rate of rats exposed in utero. Based on these studies, and studies of the hypothalamic control of the reproductive system, we propose to compare offspring of rats exposed to chronic 35% ethanol-derived calories with isocaloric controls on the following measures: a) The number of growth hormone releasing factor (GRF) neurons, somatotropin release inhibiting factor (SRIF) neurons, and the number of luteinizing hormone releasing hormone (LHRH) neurons in the hypothalamus. The number and activity of these cells is related to the pituitary release of growth hormone, luteinizing hormone, and follicle stimulating hormone. b) The size and immunohistochemical composition of the anterior pituitary, where the somatotropic and gonadotrophic cells produce their hormones. c) The average circulating levels of growth hormone an luteinizing hormone, and the response of each to stimulation of the pituitary. d) The pattern of postnatal growth from birth to 60 days. e) The age of puberty, as judged by vaginal patency and estrous cyclicity in females, and by testis descent in males. f) The histological development of the male and female gonad at 4, 35, and 60 days. While these measures will not assay every way in which the systems could be deficient, they will evaluate the most likely symptoms and sources of endocrine disturbances, filling a crucial gap in the FAS literature, and, perhaps, suggesting clinical solutions to some features of the syndrome.
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1996 — 2000 |
Rodier, Patricia M |
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. |
Environmental Triggers and Neural Tube Injury @ University of Rochester
nerve injury; environmental toxicology; embryo /fetus toxicology; neural plate /tube; developmental neurobiology; craniofacial; neuroanatomy; disease /disorder model; model design /development; genetic disorder; thalidomide; brain stem; dorsal motor nucleus; valproate; congenital nervous system disorder; early embryonic stage; gene expression; neural degeneration; autism; neuropsychology; animal developmental psychology; retinoate; human tissue; laboratory mouse; postmortem;
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1997 — 2000 |
Rodier, Patricia M |
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. |
Early Developmental Genes and Autism @ University of Rochester
It has long been though that injuries during the first states of brain development either kill the embryo, result in neural tube defects, or are followed by complete recovery of the CNS, making this period of little interest to neurotoxicologists. However, new evidence suggests that injury during the earliest stages of brain development may be of great importance. Studies of mice transgenic for targeted disruptions of genes involved in segmentation of the hindbrain reveal that whole rhombomeres can be lost without obvious changes in the development of the rest of the CNS. Thus, it is not true that massive lesions of the neural tube either stop development or recover. Are there human conditions of unknown cause with brain stem lesions due to injury during neural tube closure? We propose that this pattern is the one that leads to autism. In a recent report, thalidomide cases exposed during neural tube closure exhibited an autism rate of over 30%, along wit neurological symptoms of brain stem injury. Using valproic acid, we have reproduced features of the thalidomide cases in a rat model. These animal also have abnormalities of the cerebellum similar to those reported in human cases of autism. To test the hypothesis that autism arises from injury to the closing neural tube, we examined an autistic autopsy case and found evidence of an early injury to the brain stem. Because the neuroanatomy of the autopsy case reproduces several features of the Hoxa-1 knockout mouse, we now propose to test the hypothesis that this gene or related early developmental genes are the source of the genetic liability in autism. We shall sequence the Hoxa-1 gene in autopsy cases and in familial and sporadic living cases of autism, looking for a mutation. Cases of autism will be characterized as t symptoms of the disorder, cognition, language, neurology (including motor function), and physical anomalies. When a mutation is identified, we shall proceed to study the pattern of inheritance of the gene and of the symptoms, testing family members of cases with mutations genetically and behaviorally. Unlike other attempts to identify a genetic cause of autism, this one is based on data about the developmental origin and neuroanatomical phenotype responsible for some cases of the disease. Identification of a mutation underlying autism would allow a clinical test r the deficit and the creation of transgenic animals in which teratogens coul be tested for the potential to trigger the disease.
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1998 — 2002 |
Rodier, Patricia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Genotype and Phenotype in Autism and Related Behaviors @ University of Rochester
Identification of the embryonic stage when injury can cause autism has led to the insight that the disorder is initiated by changes in the developing brain stem. The shortening of the hindbrain and loss of cranial nerve neurons in an animal mode of the insult and a human cause of autism resemble features of the Hox-1 transgenic knockout mouse. Thus, it is now possible to suggest a unifying hypothesis regarding the multiple etiologies of autism. We propose that teratogens and genetic defects lead to similar developmental changes in the brain stem because mutations of early developmental genes are the cause of familial cases and the teratogens which cause the disease act by interfering with function of the same genes. The new finding that one of the candidate genes is abnormal in some cases autism supports this hypothesis. This project will continue our attempt to identify genetic causes of autism based on data about the developmental origin and neuroanatomical phenotype responsible for some causes of the disease. We shall examine early developmental genes for mutation in cases of autism, Asperger's syndrome, Moebius syndrome, developmental language disorder with semantic-pragmatic features, and normal controls. It is our hypothesis that these syndromes are related to autism not only behaviorally, but etiologically, as well. Minor physical anomalies and neurological symptoms which have fixed the time of injury in some cases of autism will be investigated in all groups to determine whether there is evidence for the same time of origin in the related disorders. Behaviors affected in autism, including language, emotion, and cognition, will be described in each patient, and the data from biological markers and behavioral descriptions will be used to searched for clusters of cases related in phenotype or etiology. By evaluating the characteristics of all these groups with the same measures, we hope to define relationships that expand or refine the definition of autism. The goal of these studies is to produce biological markers for human causes of autism and provide genetic constructs for animal models of genetically- induced autism. The models will be created in Project I and tested behaviorally in Project II.
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1998 — 2007 |
Rodier, Patricia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. U19Activity Code Description: To support a research program of multiple projects directed toward a specific major objective, basic theme or program goal, requiring a broadly based, multidisciplinary and often long-term approach. A cooperative agreement research program generally involves the organized efforts of large groups, members of which are conducting research projects designed to elucidate the various aspects of a specific objective. Substantial Federal programmatic staff involvement is intended to assist investigators during performance of the research activities, as defined in the terms and conditions of award. The investigators have primary authorities and responsibilities to define research objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations and conclusions of their studies. Each research project is usually under the leadership of an established investigator in an area representing his/her special interest and competencies. Each project supported through this mechanism should contribute to or be directly related to the common theme of the total research effort. The award can provide support for certain basic shared resources, including clinical components, which facilitate the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence. |
Genotype and Phenotype of Brainstem Injury in Autism @ University of Rochester
Autism is a neuro-developmental disorder. This program will make use of new discoveries to bring research on autism into the context of modern developmental biology, neurobiology, and molecular genetics. Identification of the embryonic stage when injury can cause autism has led to the insight that the disorder is initiated by changes in the developing brain stem. The shortening of the hindbrain and loss of cranial nerve neurons in an animal model of the insult and a human case of autism resemble features of the Hoxa-1 transgenic knockout mouse. This suggests a unifying hypothesis regarding the multiple etiologies of autism: We propose that teratogens and genetic defects lead to similar developmental changes in the brain stem because mutations of early developmental genes are the cause of familial cases and the teratogens which cause the disease act by interfering with functional of the same genes. The new finding that one of the candidate genes is abnormal in some cases of autism supports this hypothesis. In Project I. Animal Models of Autism and Mechanisms of Injury, we shall compare the effects of valproic acid, hexanoic acid and retinoic acid on the Hox gene cascade, using mice transgenic for lacZ markers of Hoxa-1 expression, in situ hybridization for markers of the rhombomeres, and staining for neurofibrils. We shall develop animal models transgenic for human mutations involved in autism. Finally, we shall test for interactions between early developmental gene mutations and teratologic exposure. The goal is to understand how teratologic agents and genetic anomalies produce similar effects on the hindbrain. Project II. Behaviors Discriminating Autism in Humans and Animals, is an investigation of two behavioral tasks with promise to discriminate autism from other developmental disabilities. Both the conditioned eye-blink response and an attention task have already been shown to be affected in autism. The long- term goal is to develop animal tasks that can serve as markers of the injury that causes autism so that animal models can be tested for parallelism to the human disorder. Project III. Genotype and Phenotype in Autism and Behaviorally-Related Disorders, will assess behavioral symptomatology, minor physical anomalies, and neurological/ophthalmological deficits, and mutations of early developmental genes in four developmentally disabled groups (autism, Asperger syndrome, Moebius syndrome, and semantic-pragmatic language disorder) and normal controls. The goal is to determine whether the phenotypic or genotypic features of these disorders indicate a common etiology.
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2003 |
Rodier, Patricia M |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Administrative Core @ University of Rochester |
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2003 — 2007 |
Rodier, Patricia M |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Genotype and Phenotype of Response to Treatments of Autism @ University of Rochester
STAART CENTER: Individual differences in response to treatments of autism spectrum disorders (ASDs) present a serious problem in choice of treatment. If we could predict in advance which children would benefit from the available interventions and which would not, children could be matched to treatments. On the other hand, individual differences in response to treatment may represent an opportunity for studies of the etiology of autism. Responders and non-responders are likely to represent different subsets of the spectrum that may be genetic in origin. Along with other phenotypic characteristics of children with ASDs, response to treatment is a dimension that deserves investigation as a possible way to stratify the spectrum for genetic studies. We propose studies of children's response to two of the most commonly used treatments of ASDs: early intensive behavioral intervention (Project I) and the gluten-free, casein-free diet (Project II). Each treatment project is accompanied by a related neurobiological investigation. Project III is an examination of the neurobiology of facial expression and imitation, which are important in the behavioral interventions under study in Project I. Project IV is an investigation of the sense of taste in both humans and animals, based on preliminary evidence that children with ASDs have dysfunction in this modality. It addresses dietary issues broader than the specific diet under study in Project II. Each Project has a genetic component, to explore the relationship of six suspected candidate genes to treatment response and other phenotypic characteristics of children with ASDs. A Genetics Core will provide the molecular testing for these studies. Each Project will use an Assessment and Records Core for characterizing participants and/or identifying and recruiting appropriate participants. An Administrative core will oversee the program, providing budgetary oversight, internal and external review of progress, statistical services, interactions with the community, and regular interactions between investigators. This proposal takes advantage of an unusual environment. The availability of intensive early behavioral intervention at public expense facilitates treatment studies. A large population of children with ASDs and families anxious to participate in research facilitate recruitment. The presence of a biologically-oriented CPEA complements the Projects of the STAART Center.
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2004 |
Rodier, Patricia M |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Eyeblink Conditioning &Study of Neurobehavior Disorders @ University of Rochester
neuropathology; disease /disorder etiology; autism; conditioning; reflex; cognition; prosencephalon; brain stem; cerebellum; neuroanatomy; behavioral /social science research tag; human subject; clinical research;
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2004 |
Rodier, Patricia M |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Genotype/Phenotype in Brain Stem Injury in Autism @ University of Rochester
neuropathology; neurogenetics; phenotype; autism; developmental neurobiology; developmental genetics; brain injury; brain stem; genotype; brain morphology; gene mutation; teratogens; clinical research;
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2005 |
Rodier, Patricia M |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Eyeblink Conditioning and the Study of Developmental Neurobehavioral Disorders @ University of Rochester |
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