Richard Rogers - US grants

Until recently, the precise nature of hypothalamic control over vagal neurons controlling gastric motility, bloodflow and secretion was a matter for speculation. This was due largely to the fact that hypothalamic lesions and stimulation (the predominant means of study) produced equivocal gastrointestinal effects. Recent advances in neuroanatomical tracing techniques have revealed that only one direct hypothalamo-vagal motor projection exists. This projection is derived entirely from the paraventricular nucleus of the hypothalamus. The experiments presented herein will begin the physiologic and pharmacologic description of this projecting by utilizing advanced neurophysiological methods coupled with classical measures of gastric function. In particular, we will apply single-neuron recording techniques to physiologically identified gastric vagal neurons and paraventricular hypothalamic neurons. By using microstimulation and spike-triggered averaging methods the nature of the direct hypothalamic-gastric vagal projection will be estimated. Next, we will microiontophorese putative peptide neuro-effectors onto identified gastric vagal neurons in an attempt to mimic the effects of paraventricular hypothalamic input upon these parasympathetic preganglionic neurons. Finally, the physiological significance of these observations will be tested by repeating them while recording indices of gastric acid production and gastric motility. The objective of this and succeeding studies is the unequivocal elucidation of the nature of direct hypothalamic projections upon parasympathetic preganglionic neurons which regulate gastric function. Given that a variety of stress-induced gastrointestinal pathology, particularly ulcers, may be neurogenic in origin, the results of these studies may demonstrate the way in which the hypothalamus might be directly involved in the production of such pathology.

The proposed project is designed to provide insight into the neurophysiological relationships between hypothalamic and limbic activity and vagal control over gastric function which are important to an understanding, and eventual management, of stress-induced gastric pathology. It addresses recent findings which indicate that messenger peptides localized in the pre-vagal forebrain nuclei (paraventricular neuleus of the hypothalamus (PVN); bed nucleus of the stria terminalis (BNST); and the central nucleus of the amygdala (CNA) and medullary vagal neurons either exacerbate or suppress the development of stress-induced gastric ulcers. The overall objective of this project is to determine whether neuropeptides which profoundly affect gastrointestinal function, when injected into the brain, do so by acting within a system of forebrain neurons connected directly with second-order neurons in sensory pathways from the stomach and the medullary neurons that project to the stomach. Specifically, the effects of neural activity in the PVN, CNA, and BNST on gastric vagal neurons will be examind using electrical or glutamate microstimulation in conjunction with electro-physiological recording and spike-triggered averaging techniques. Peptides known to be localized within these hypothalamic nuclei, as well as antagonists, will be microinjected into the brain. We will evaluate the peptidergic receptors involved in the hypothalamo-vagal pathway. Gastric motor function will be monitored with extraluminal strain gauges or gastric acid secretion will be measured in order to determine the effect of central nervous system manipulations.

Pancreatic polypeptide [PP] is released from pancreatic endocrine cells following feeding. The release of this peptide from the pancreas:, produces a reduction in pancreatic exocrine secretion, as well as changes in gastrointestinal secretion and motility. PP action on digestion has been difficult to explain in that its acute actions on digestive functions are not direct. Intact vagal efferent innervation is required for PP effects, a fact that lead to speculation that PP may control vagal efferent projections to the gut and pancreas through endocrine action on brainstem structures. This view recently received significant reinforcement with the finding that the dorsal vagal complex in the medulla contains a high concentration of saturable and specific receptors for PP. Thus, pancreatic polypeptide [PP] may represent a unique digestive endocrine feedback control signal which directly regulates the excitability of vago-vagal reflex circuits to control digestive functions. We plan to apply two separate methods to test this hypothesis directly. First, we will apply PP directly to the dorsal vagal complex using quantitative micropressure injection techniques. This will establish if PP can act via vago-vagal reflex circuits to produce measurable changes in gastrointestinal and/or pancreatic functions. Studies will be performed in both anesthetized and acute, awake preparations. Next, we will determine how PP affects the function of neurophysiologically identified neuronal components of vago-vagal circuits in the brainstem in the intact, anesthetized rat. These studies will determine how PP acts on individual identifiable neuronal components of digestion control reflexes. Together, these studies will provide an indication of how this unique pancreatic endocrine hormone can control an array of digestive functions by acting on vagal circuits in the brainstem.

DESCRIPTION (Adapted from the Abstract): A long-term goal of the Principal Investigator is to explain the physiological mechanisms responsive for the coordination of digestive functions with changes in ingestive behavior. A significant manifestation of the relation between ingestive behavior and digestion involves the suppression of gastric functions and the associated nausea and malaise, lost of appetite, vomiting, and diarrhea that are common symptoms associated with infectious illness and malignancy. The pathophysiological changes are though to be mediated by cytokines liberated by the host in response to antigenic challenge. Yet, the specific site(s) or mechanisms of action of these cytokine-induced responses are not clear. Tumor necrosis factor-alpha (TNF-alpha) is one of the first cytokines to be released and plays a pivotal role in initiating the cascade of cytokine release in the host response of challenge. TNF is thought to be the primary mediator of the gastrointestinal (GI) symptoms evoked during sepsis, malignancy, and other disease processes associated with the suppression of feeding behavior in chronic infectious and malignant disease. Recent studies have demonstrated that the dorsal vagal complex (DVC) is devoid of a blood-brain and that large peptides and proteins (e.g., hormones, immunoglobulin, complement, cytokines) in the circulation readily traverse the extracellular spaces of this area. The DVC contains the circuit through which the brain ultimately controls digestive function. The highest density of saturable, TNF-alpha binding sites has been demonstrated in the brainstem. Thus, the Investigator hypothesizes that TNF-alpha may represent a unique chemical "afferent" signal which directly alters vago-vagal reflex circuit function, resulting in a suppression of gastric functions during infectious and carcinogenic disease. In the proposed experiments, the Investigator focuses on the acute mechanisms of action of the cytokine TNF-alpha within the DVC. From these neurophysiological studies, he and his associates will provide information on how TNF-alpha can control digestive functions by acting on vagal circuits within the brainstem, and a foundation for future studies examining the specific mechanisms of actions of cytokines on the central circuits which may co-regulate digestive functions and ingestive behavior during chronic disease.

This four-year Nanoscale Interdisciplinary Research Team (NIRT) project at the University of Florida with ProfessorCharles R. Martin as principal investigator, conducts a broad-based and systematic investigation of the development of smart nanotubes that are bioengineered and tailor-designed so as to accomplish specific biomedical/biochemical functions. Silica asn polymeric nanotubes will be extensively used in this research effort. Functionalized biodegradable and biocompatible poly( (lactide) nanotubes will be prepared. The objective of the research program include: (1) to show that the chemical microenvironment within biochemically-functionalized nanotubes can be fine-tuned so as promote specific desired biochemical processes; (2) to show that such nanotubes can be capped via self-assembly chemistry with nanoparticle caps; (3) to demonstrate that these nanoparticle caps can be attached via chemical bond that dissociate when a specific intercellular chemical signal is detected; (4) to show that such nanotubes can be tagged on their outer surfaces with antibodies that recognize specific cell types; and (5) to prove that all of these concepts can be used in concert to design new nanotube-based DNA transfection vechicles that deliver genetic material to specific desired cell types.

This proposal requests funding for a Global Reseach Training in Population Health (GRTPH) program that links the University of Colorado Population Program and two outstanding research and training groups in sub-Saharan Africa - at the University of the Witwatersrand in Johannesburg, South Africa (Wits) and the African Population and Health Research Center in Nairobi, Kenya (APHRC). These two institutions each run longitudinal health and demographic studies, one rural, the other urban. The program is intended to address needs for trained demographers and population scientists in low- and middle-income countries who can be involved in the measurement, monitoring, and evaluation of central population health issues and who can conduct research that meets international standards on population health, migration, environment, and their interrelationships. It builds on the demonstrated strengths of each unit in carrying out multidisciplinary and interdisciplinary research in these areas and the commitment each has to training. It is based on continuing relationships among institutions, rather than single investigators. Specifically, it builds on the African Population Studies Research and Training Center at CU, a collaborative effort among these three institutions. The program currently consists of (1) a postdoctoral fellow partnership program;(2) intensive visits to CU by African trainees;(3) African student mentoring and involvement in collaborative research;(4) conference on training/curricula for programs based in African institutions;(5) an annual Colloquium in which all three groups participate;(6) small grants for pilot collaborative research;(7) grant preparation and administration assistance;(8) strong continuing institutional ties and senior faculty/ administrator involvement: and (9) ongoing collaborations across institutions emphasizing health, migration, and environment and their interconnections. To this existing program, the GRTPH program would add: (1) Postdoctoral fellowships open to African scholars with industrialized-country Ph.D.'s to return to one of the two partner institutions;(2) Fellowships for graduate students at Wits;(3) Internships for Wits graduate students at APHRC;and (4) Short courses at Wits and APHRC offered by APHRC senior staff and CU staff. This program is especially intended to increase research and training capacity at Wits and APHRC while it increases African research and collaborations at CU. Through continued interactions, training, and collaborative research, this network is well-positioned to contribute in powerful ways to expanding training opportunities of African junior investigators and cultivating current and forging new collaborative research and training relationships, aimed at contributing to fuller and better understanding and, ultimately, to improvement of African population health.

The Supreme Court in its landmark decision of Miranda v. United States established constitutional protections for suspects in custody. While mapping out the basic components of Miranda warnings (e.g., right to silence), the Court has consistently declined to specify the language of such warnings or waivers. As a result, more than 800 different versions of Miranda have been identified that vary markedly in length from 21 to 408 words and reading level from grade 2.8 and post-college.
In an analysis of detainees with observations taken at multiple time points following arrest, this project identifies psychological vulnerabilities that impair Miranda comprehension and subsequent decision making. Potential vulnerabilities include limited intelligence, learning disabilities, and mental disorders. Beyond psychological vulnerabilities, suspects may have impaired thinking patterns, called cognitive distortions, which affect their abilities to rationally decide whether to give up their rights to silence and counsel. This project examines how psychological vulnerabilities and cognitive distortions may impair suspects' constitutional protections. They are addressed for representative Miranda warnings written at easy (less than grade 6), moderate (grade 8 to 10), and difficult (grade 12 or higher) reading levels. They are also evaluated for the type of warning presentation (oral versus written).
A second objective is the development of simplified Miranda warnings that can facilitate procedural justice by informing custodial suspects with easily understood information. In doing so, the study identifies prototypical components of Miranda warnings that are brief, clear, and easily read. These simplified warnings are tested for their clarity and ease of comprehension. Finally, the research is expected to contribute to the development of reliable and valid Miranda measures for the standardized assessment of Miranda vocabulary, comprehension of Miranda warnings, and decision-making about Miranda waivers.

SES-0927370
Richard Rogers
Bethany Everett
University of Colorado Boulder

This dissertation research will investigate health disparities during the transition from adolescence to young adulthood. Sexual minorities face higher levels of structural and interpersonal discrimination, and a growing body of research is beginning to document their effect on the health of sexual minority populations. Therefore, this research will explore the following questions: (1) What are the links between sexual orientation and health; (2) What role do socio-demographic and social-ecological factors play in moderating these relationships; and (3) Are variations in the timing and pattern of same-sex orientated attraction, behavior, and identification differentially associated with health outcomes? This research will contribute to the literature by employing multiple indicators of sexual orientation available in the National Longitudinal Study of Adolescent Health (Add Health). Specifically, this research will investigate a wide variety of health-related outcomes, including access to and use of health services; alcohol, tobacco, and drug use; mental health; and a series of biomarkers designed to measure anthropometric, cardiovascular, metabolic, and inflammation functioning, novel for this population. In addition to using these cutting-edge data, I will employ a series of innovative statistical techniques, including latent class trajectory, structural equation, and multilevel modeling. Moreover, this research will contribute to an emerging interdisciplinary bio-behavioral framework within the field of sociology that stresses the synergistic impact of individual, environmental, and biological processes on health.

This proposal specifically addresses a target population and goals identified by the Healthy People 2010 initiative (NCHS 2000). It will generate important findings for public health policy makers by documenting previously unexplored longitudinal trends. Moreover, the study provides a unique opportunity to examine health disparities among a vulnerable population distributed across all race/ethnic and socioeconomic groups, and in a variety of contexts. The research will produce results regarding healthy adolescent development, including the impact of discrimination on health, which may be generalizable to other minority populations.

More than a million juvenile suspects are arrested annually and taken into custody. Prior to any confessions or other statements, they must be informed of their Constitutional rights against self-incrimination via Miranda warnings. Juvenile warnings vary in how they are presented (i.e., oral, written, or both) and in their reading levels. Using representative juvenile Miranda warnings, this project is the first to examine how much juveniles understand and apply to their decision-making about whether to exercise their Constitutional rights. The project uses two relevant samples: at-risk youth in juvenile justice alternative education and juvenile detainees in custody. The project also investigates several misconceptions about Miranda warnings that can nullify any rational reasoning about Constitutional protections. For example, many adolescents believe that their silence can be used as incriminating evidence, which might affect their decision whether to talk to police. Two aspects of Miranda misconceptions are studied: (1) their initial beliefs and (2) any improvements as a result of being Mirandized.

This research has far-reaching implications for public policy and appellate court decisions. In 2010, the American Bar Association recognized the national problem of providing juvenile suspects with Miranda warnings they could not understand. This project should assist their initiative for by identifying current problems in the administration of juvenile advisements. The U.S. Supreme Court has recently decided several cases, which established that juveniles be dealt with differently in light of their maturity and intellectual development. In 2011, the U.S. Supreme Court directly addressed juvenile Miranda issues, holding that juvenile suspects are not "miniature adults" and that age is relevant in considering the validity of Miranda waivers. The current research will help to inform the state and federal courts regarding the potential provision of additional Miranda protections for juvenile offenders.

? DESCRIPTION (provided by applicant): This project will develop an in-depth understanding of early life mortality (ages 0-24) in the United States in the context of substantial racial/ethnic inequality and very rapid socioeconomic and family changes that have occurred in recent decades. Aims: We will document the associations between the risk of overall and cause-specific early life mortality with: parental socioeconomic status (SES), family structure, and race/ethnicity. We will do so for demographic subpopulations, for the contemporary time period and with regard to changes over the past 25 years, and for geographic areas of the country. Significance: Alarmingly, the United States ranks dead last in comparison to 16 high-income counterparts, usually by a sizeable margin, in age-specific early life mortality rates. Our proposed research is highly significant because it focuses on a crucial public health problem, addresses major gaps in knowledge regarding basic yet critical contemporary patterns of early life mortality, increases our limited knowledge about how trends of US early life mortality have unfolded over the last 25 years, and informs theoretical debates about changing patterns of mortality in an increasingly stratified society. Innovation: The project is highly innovative because it grounds the work in a conceptual framework that highlights the diverging socioeconomic and family contexts in which infants, children, and youth are living; devotes serious attention to the changing racial/ethnic composition of the population; and attend to both geographic variations and temporal trends. Framework: Our conceptual framework focuses on three interrelated resources-SES, family structure, and race/ethnicity-that are important in differentiating the survival prospects of individuals. Children living with the most highly educate parents are now supported by more economic and parental time resources than ever before while children living with the least educated parents lag further behind their counterparts than they did in the 1970s. Family structure changes are associated with and may be exacerbating these educational differences in children's resources. Such social and economic changes and continued racial/ethnic inequality may have pronounced effects on early life mortality risks, with particularly detrimental consequences for the most disadvantaged demographic subgroups living in the most disadvantaged geographic contexts. Data and Methods: We will primarily employ demographic methods and hazards modeling to exploit the two largest and most comprehensive US data sets extant for analyzing early life mortality: the 2013 release of the 1986-2011 National Health Interview Survey-Linked Mortality Files and the 1989-2008 NCHS Linked Cohort Birth/Infant Death Files. Conclusion: This project has enormous potential to produce new and important substantive and policy-relevant information about US early life mortality, a critical but woefully overlooked area of study. Ultimately, we expect to identify ways for US early life survival rates to match if not surpass rates for other high income countries.

PROJECT SUMMARY In response to RFA-HD-15-009 for the Population Dynamics Centers Research Infrastructure FY 2015 (P2C), the University of Colorado at Boulder Population Center (CUPC) requests five years of funding from NICHD for infrastructure support. With its first center award in 2010, CUPC made substantial progress in the size and quality of the faculty affiliates, the number of external grants, and its professional presence and scholarly influence in population research. With continued center funding, we propose to build on this progress with innovative work in our primary research areas; collaborative ties across disciplines; institutional ties with colleagues in other universities and nations; mentoring and support for a group of promising junior faculty; center support for excellence in population science research; and increased external funding. Toward these goals, the proposal describes the three primary research areas of the center: health and mortality; migration and spatial demography; and environmental demography. It also describes plans to scale up funding support, advance several new research initiatives, target novel and significant research with center funding, and bring in scholars with new expertise and shared interests in population topics. The activities all aim to increase the pace and impact of center research. The center requests three infrastructure cores: The Administrative Core provides crucial services to all affiliates, including clerical, bibliographic, editing, and grants management support for research projects. The Development Core provides seed awards to allow researchers ? particularly junior affiliates ? to begin and develop innovative research and improve chances for external funding. It further provides leadership for several new initiatives that expand our primary research areas. The Scientific/Technical (or Data) Core deals with issues relating to the access, management, processing, and analysis of data. It supports a first-rate computing and technology environment for handling large and complex data sets and makes use of affiliate expertise for statistical training and consultation.

DEVELOPMENT CORE PROJECT SUMMARY The Development Core represents an important component of the University of Colorado?s Population Center (CUPC) proposal in response to RFA-HD-20-015 for the Population Dynamics Research Infrastructure Program FY 2020 (P2C). CUPC requests renewal of infrastructure support for the five-year project period 2020?2025. Fueled by NICHD funds, the Center is firmly established as the hub of population science at CU and CUPC?s Development Core has been redesigned to build on CUPC?s strong momentum. In the next five years, the Development Core has three specific aims: (1) increase the scientific impact, innovation, and productivity of CUPC's population researchers; (2) increase CUPC affiliate's competitiveness for external funding in population science; and (3) continue and increase support for early investigators in population science. A variety of new and reconfigured activities are proposed to meet these aims. To enhance productivity and innovation, as well as to increase cohesiveness within primary research areas, in the past five years, thematic working groups have been established with faculty leads. These groups have had notable success in spurring new research collaborations and in the next grant cycle, resources are requested to support innovative activities within the working groups. Also, to increase external funding competitiveness, CUPC will develop a grant writing workshop to build on the already-impressive success of the Center?s energetic, early stage investigators. Finally, substantial new investment from CU Boulder provides resources to raise the funding on seed grants and increase the pool of available funds. Throughout, the CUPC director and Development Core director collaborate to ensure that early stage investigators are centrally considered within investments with a target of this group receiving at least 50% of seed grants in the next five years. Faculty accomplishments have been recognized at the university scale as evidenced by generous, new support from across the Boulder campus. A formalized Memorandum of Understanding with CU Denver expands the Center with new funding, space and collaborative commitment. These combine to lay a foundation for CUPC?s continued growth in productivity, innovation and impact and the Development Core has been redesigned to support the Center in this growth.