December 2, 2010 - This PAR has been reissued as (PAR-11-051).
NOTICE: Applications submitted in response to this Funding Opportunity Announcement (FOA) for Federal assistance must be submitted electronically through Grants.gov (http://www.grants.gov/) using the SF424 Research and Related (R&R) forms and the SF424 (R&R) Application Guide.
Purpose. This FOA encourages projects that enhance the state-of-the-science on the molecular and cellular, genetic and epigenetic mechanisms involved in the production of adverse drug reactions in children.
Mechanism of Support. This FOA will utilize the NIH Research Project Grant (R01 grant) award mechanism and runs in parallel with an FOA of identical scientific scope, PAR-08-249, that solicits applications under the R03 grant mechanism.
Funds Available and Anticipated Number of Awards. Awards issued under this FOA are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. The total amount awarded and the number of awards will depend upon the mechanism numbers, quality, duration, and costs of the applications received.
Budget and Project Period. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds.
Application Research Strategy Length: The R01 application Research Plan component of the PHS398 (Item 3) may not exceed 12 pages, including tables, graphs, figures, diagrams, and charts. See https://grants.nih.gov/grants/funding/funding_program.htm.
Renewals Applicants may submit a renewal application.
Special date(s) This FOA uses non-standard dates. See Receipt, Review and Anticipated Start Dates.
The objective of this announcement includes research on the role of ontogeny and the characterization of pharmacogenetic and developmental variations of drug metabolizing enzymes (DMEs), transporters, ion channels, receptors and signaling pathways that are responsible for drug toxicity in the pediatric population. Research on the role of ontogeny in the production of, and immune responses to, reactive metabolites and research on the efficiency of detoxification mechanisms are particularly emphasized. The development of adequate animal and in vitro models to spur discovery of the mechanisms of hypersensitivity reactions in children and the identification of toxicity biomarkers are an important part of this initiative. Another important objective will be to determine whether, within the developmental continuum between birth and adolescence, there are periods of increased vulnerability to drug toxicity.
This FOA also invites application that will investigate 1) the underlying molecular, and biochemical mechanisms, including genetic vulnerability, by which drugs of abuse induce toxicity in children as stated in the FOA and 2) those that were exposed to drugs of abuse maternally (intrauterine, milk etc). Some of the examples of drugs of abuse to be investigated in this FOA are nicotine, cocaine, marijuana, tobacco, opiates and heroin, methamphetamine, 3,4-methylenedioxymethamphetamine, and LSD.
Adverse drug reactions (ADRs) are an important clinical problem and represent a major contributor to mortality and morbidity in adults. Although most research to date has largely been confined to adults, the significance of ADRs in children has been increasingly recognized. ADRs in children differ from those manifested in adults in frequency, nature, and severity.
Upon exposure to some drugs, infants and young children are at a greater risk than adults for developing ADRs (e.g., acute central nervous system and hyperpyretic reactions to anticholinergic drugs such as atropine and scopolamine, and life-threatening adverse reactions to valproic acid). Conversely, children may also be less susceptible than adults to toxic reactions from other drugs. For example, infants are less likely to develop ototoxicity or nephrotoxicity from aminoglycosides, and the hepatocellular damage resulting from an acute acetaminophen overdose is considerably milder in young children than in adults.
Type A reactions are dose-related and can be predicted from the known pharmacokinetics and/or pharmacodynamics of the drug. For example, infants, especially preterm infants are at risk for this type of ADR because of immaturity of their drug metabolizing enzymes (DMEs). The developmental patterns of many biotransformation enzymes (both Phase I and Phase II) have not been sufficiently characterized in children. There is evidence, however, that CYP3A4 activity increases in early childhood and surpasses the enzyme activity in adults. This knowledge raises the possibility that increased activity of some P450 isoforms may be a pathogenic mechanism in the generation of reactive metabolites involved in idiosyncratic reactions. Under normal circumstances, reactive metabolites are inactivated by detoxification mechanisms. The glutathione pathway is important in the detoxification of exogenous and endogenous compounds and in the cellular defense against oxidative stress. The ontogeny of the enzymes involved in glutathione conjugation reactions (e.g., glutathione-S-transferase and glutathione peroxidase) and the factors that determine the size of the glutathione pool have not been sufficiently characterized in children. The mechanisms involved in idiosyncratic reactions are poorly understood. Circumstantial evidence points to a major role of reactive metabolites interacting with elements of the immune system. An important pathogenetic hypothesis to be tested is whether an increased production of reactive metabolites is associated with the increased activity of certain drug metabolizing enzymes (e.g. cytochrome P 450 3A4, 2C9 and 1A2) that occurs in young children. An imbalance favoring the development of idiosyncratic reactions may occur if a relative deficiency in drug detoxification mechanisms is also present. Often, idiosyncratic (Type B) reactions are mediated by drug metabolites, directly or by way of an interactions with a secondary cellular target. Rarely a Type B ADR may be due to cross reactivity between components of a pathogen and the host.
Adverse drug reaction (ADR)-dependent toxicity caused by drugs of abuse in children is a major problem in this country. Children may be exposed to drugs of abuse in various ways including: in utero exposure during pregnancy; through breast feeding; and postnatal direct exposure during adolescence period. Several studies suggest that both prenatal and postnatal exposure to drugs of abuse can lead to toxicity of various organs/systems in children. The adverse effects on nervous system (brain) include reduced cortical gray matter and total parenchymal volume, cognitive deficits (memory and learning), impaired speech-processing ability, and increased risk for neuropsychiatric disorders. Cardiovascular anomalies associated with drugs of abuse are hypertension, tachycardia, myocardial ischemia, myocarditis, and cardiomyopathy. Breathing secondhand tobacco smoke increases risks for sudden infant death syndrome, acute respiratory infections, asthma, middle-ear disease, and multiple sclerosis in children. Exposure to drugs of abuse may also render children susceptible to opportunistic infections such as HIV, HCV, Streptococcus pneumoniae. Understanding the mechanisms of toxicity may help identify targets of interventions for treatment or preventive measures.
Investigations to elucidate drug vulnerability, tolerance, physical dependence, learning, memory, cognition and developmental biology in pediatric populations exposed to drugs of abuse vs. normal.
Role of epigenetic factors to explain or predict developmental differences in the expression of ADRs.
Understanding the mechanisms whereby drugs of abuse exposure renders children susceptible to HIV and HCV infection.
This Funding Opportunity Announcement (FOA) will use the NIH Research Project Grant (R01) award mechanism.
This FOA uses Just-in-Time information concepts. It also uses the modular as well as the non-modular budget formats (see https://grants.nih.gov/grants/funding/modular/modular.htm).
Specifically, if you are a U.S. organization and are submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs), use the PHS398 Modular Budget component provided in the SF424 (R&R) Application Package and SF424 (R&R) Application Guide (see specifically Section 3.4, Modular Budget Component, of the Application Guide).
U.S. applicants requesting more than $250,000 in annual direct costs and all foreign applicants must complete and submit budget requests using the Research & Related Budget component found in the application package for this FOA. See NOT-OD-06-096, August 23, 2006.
Alaska Native and Native Hawaiian Serving Institutions.
Applicants may submit a resubmission application, but such application must include an Introduction addressing issues raised in the previous critique (Summary Statement).
To download a SF424 (R&R) Application Package and SF424 (R&R) Application Guide for completing the SF424 (R&R) forms for this FOA, link to http://www.grants.gov/applicants/apply_for_grants.jsp and follow the directions provided on that Web site.
Prepare detailed budgets for all applications (that is, complete the Research & Related Budget component of the SF424 (R&R) application forms not the PHS398 Modular Budget component)(see NOT-OD-06-096).
Comply with the format specifications, which are based upon a standard U.S. paper size of 8.5 x 11 within each PDF.
If appropriate, request funds for up to 8% administrative costs (excluding equipment) (see NOT-OD-01-028, March 29, 2001).
When submitting a modular budget, the prime institution completes the PHS398 Modular Budget component only.Information concerning the consortium/subcontract budget is provided in the budget justification. Separate budgets for each consortium/subcontract grantee are note required when using the Modular budget format. See Section 3.4 of the Application Guide for further instruction regarding the use of the PHS398 Modular Budget component.
Applications may be submitted on or after the opening date and must be successfully received by Grants.gov no later than 5:00 p.m. local time(ofthe applicant institution/organization)on the application submission/receipt date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the receipt date(s) and time, the application may be delayed in the review process or not reviewed.
If the AOR/SO chooses to Reject the image after the submission deadline for a reason other than an eRA Commons or Grants.gov system failure, a changed/corrected application still can be submitted but it will be subject to the NIH late policy guidelines and may not be accepted. The reason for this delay should be explained in the cover letter attachment.
Resubmission Applications: When reviewing a Resubmission application (formerly called an amended application), the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.
Budget and Period of Support: The reasonableness of the proposed budget and the appropriateness of the requested period of support in relation to the proposed research may be assessed by the reviewers. The impact/priority score should not be affected by the evaluation of the budget.
Applications from Foreign Organizations: Whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources will be assessed.