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Genetics and pathobiology of vascular cognitive impairment.

The purpose of this Program Announcement with set-aside funds (PAS) is to invite applications to study the biological basis of vascular cognitive impairment (VCI). VCI causes a burden of illness similar to that caused by Alzheimer's disease (AD), but has been far less well-studied. Recently, however, some important strides have been made in understanding the etiology of VCI. These include the discovery of a monogenic form of vascular dementia, CADASIL, and identification of the causative gene as Notch 3. In addition, MRI and other pathological data have provided a clearer delineation of the various clinical subtypes of VCI, and awareness of the synergistic interaction between vascular and classical Alzheimer's pathologies in producing cognitive impairment. The goal of this PAS is to build on these first critical achievements to obtain a better understanding of the cellular and molecular mechanisms causing vascular, neural, and glial dysfunction in human VCI and animal models of VCI.

The number of people affected by dementia in the US is expected to increase three-fold in the next 50 years, to a total of over 13 million. The best-known form of dementia is AD, whose definitive diagnostic sign is the presence of plaques and tangles in brain neurons upon autopsy. However, a large proportion of dementia cases in the aged population are not due to AD, but rather to cerebrovascular disease. Dementia due to cerebrovascular disease is referred to as "vascular dementia", and can occur in the absence of Alzheimer's pathology. In addition to this so-called "pure" vascular dementia, there are also cases of "mixed" dementia in which cerebrovascular and Alzheimer's pathologies coexist. Recent studies suggest that pure vascular dementia and mixed dementia together comprise the majority of dementia cases in some populations.

Vascular dementia can arise from any of several cerebrovascular disease conditions, but its two major causes are focal ischemic infarcts (i.e., strokes) and subcortical ischemic vascular disease. Focal ischemic infarcts result from occlusion of large vessels, in either cortical or subcortical locations, and are accompanied by acute clinical signs of neurological impairment. (Dementia arising from large infarcts is also sometimes referred to as "multi-infarct dementia".) Subcortical ischemic vascular disease, on the other hand, results from occlusion of small vessels, and creates widespread small lesions (lacunae) and/or areas of demyelination. The areas affected are generally subcortical, including the basal ganglia, cerebral white matter and brainstem. This form of vascular disease generally does not produce sudden, acute symptoms, but rather causes longer-term, insidious changes in neurological function. In a significant portion of cases, this disease can even remain clinically silent for the life of the individual. Subcortical small vessel disease can be diagnosed by, imaging even in cases where it is clinically silent.

In recent years, the term "vascular dementia" has been replaced by the term "vascular cognitive impairment (VCI)". This change reflects the realization that cerebrovascular disease can cause significant cognitive and functional decline in the absence of dementia as defined by standard criteria. In addition, there is increasing evidence that VCI differs from AD in terms of precise range of cognitive defects associated with each disease. AD is characterized primarily by episodic memory loss due to loss of cholinergic basal forebrain neurons and their projections to the hippocampus. In contrast, VCI in its purest forms seems to be characterized more by loss of executive function and attentional mechanisms associated with prefrontal circuitry. However, the spectrums of defects seen in VCI and AD overlap substantially. This fact, together with the frequent coexistence of vascular and Alzheimer's pathologies within individual patients, renders it difficult to provide definitive diagnoses based strictly on cognitive tests.

Despite the enormous prevalence of VCI, the biological basis of this disease has been much less well studied than that of AD. This lack has been due in part to the clinical heterogeneity of the disease, and also to poor understanding of its pathology at the cellular level. Recently however, research in VCI has taken some critical first steps forward. A genetic form of vascular dementia, CADASIL, has been discovered, and the mutant gene identified as Notch 3. Previous research in animal models had shown Notch 3 to be important in early neural and vascular development. The finding that mutation of Notch 3 leads to stroke and dementia (both seen in CADASIL) suggests that the gene also plays an important role in the function or maintenance of vascular and/or neural cells in the adult. Consistent with this possibility, a transgenic mouse carrying the mutant form of Notch 3 has now been generated which shows degeneration of smooth muscle cells similar to that seen in human patients. These findings provide an important foothold for understanding the cell biology as well as the genetics of VCI. Moreover, the known interaction of Notch with the presenilin proteins suggests a juncture in the disease pathways underlying VCI and AD, which also could be further explored in mouse models.

Another major area ripe for exploration concerns the genes and other risk Factors that link vascular pathology to neural pathology or that render individuals susceptible to neuronal damage and cognitive impairment in response to cerebrovascular disease. Some progress has been made in recent years in &fining genes that predispose individuals to stroke and cerebrovascular disease per se, but no studies have yet examined genes that control the ability, of neural tissue to recover from ischemic injury. Identifying such genes would provide clear paths both to understanding the cell biology, of VCI, and also to the design of protective agents and therapeutics.

Research areas appropriate for this PAS would include, but are not imited by the following examples: 1) genetics of VCI, in both animal models and humans, in particular, identification of genes that render individuals susceptible to cognitive impairment secondary to cerebrovascular disease; 2) analysis of cellular and molecular changes occurring in vascular, neuronal, and glial cells during the development of VCI in human patients, and correlation of these with MRI signs and changes in cognitive function; 3) studies of cellular and molecular pathological processes occurring in vascular, neuronal, and glial cells in animal models of VCI, such as mouse lines carrying mutant forms of Notch 3 or the strokeprone spontaneously hypertensive rat; 4) studies of Notch 3 function in the maintenance and repair of vascular, neuronal, and glial cells in normal adult animals; studies of the cellular and molecular bases of the pathogenic actions of mutant Notch 3; 5) studies of the cellular and molecular bases of the interaction between the VCI and AD pathways (for example, studies of vascular function and pathology in animal models of AD); 6) development and characterization of new animal models for the study of VCI, and of the interaction between VCI and AD pathogenic mechanisms; 7) analysis of cognitive function in animal models of VCI, and correlation of changes in cognitive function with cellular and molecular pathologies; 8) studies on the cellular and molecular effects of hypertension, diabetes, hyperlipidemia, coagulant and anticoagulant proteins, inflammatory cytokines, and complement proteins on the vessel wall in appropriate animal models for VCI.

This PAS will use the NIH R01 and R21 award mechanism(s). As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. The proposed project period during which the research will be conducted should adequately reflect tire time required to accomplish the stated goals The R21 mechanism (see http:// grants.nih.gov/grants/guide/pa-files/PA-03-107.html) is intended to encourage exploratory and developmental research projects by providing support for the early and conceptual stages of these projects. These one-time awards support innovative, high impact research projects that assess the feasibility of a novel area of investigation or a new experimental system, include the unique and innovative use of an existing methodology to explore new scientific area, involve considerable risk but may lead to a breakthrough in a particular area, or develop new technology or methodology that could have major impact in a specific research area. Applications for R21 awards should describe projects distinct from those supported through the traditional R01 mechanism. For example, long-term projects, or projects designed to increase knowledge in a well-established area will not be considered for R21 awards. Applications submitted under dais mechanism should be exploratory and novel. These studies should break new ground or extend previous discoveries toward new directions or applications.

R21 applications may request a project period of up to two years with a combined budget for direct costs of up to $275,000 for the two year period. For example, you may request $100,000 in the first year and $175,000 in the second year. The request should be tailored to the needs of your project. Normally, no more than $200,000 may be requested in any single year. For further information on the R21 mechanism, including Institute-specific information, see http://grants.nih.gov/grants/guide/pa-files/PA-03107.html.

This PAS uses just-in-time concepts. It also uses the modular budgeting as well as the non-modular budgeting formats (see http://grants.nih.gov/ grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format. Otherwise follow the instructions fur non-modular budget research grant applications.

The National Institute of Neurological Disorders and Stroke (NINDS) has set aside a total of $2,250,000, in addition to funds available for applications sent in response to this PA that score within the NINDS payline (see NINDS Funding Strategy http://www.ninds.nih.gov/funding/ ninds_funding_strategy.him), depending on the overall scientific merit of the applications and the availability of funds throughout the duration of this solicitation (three years). The National Institute on Aging (NIA) has set aside a total of $300,000, and the National Heart, Lung and Blood institute (NHLBI) has set aside a total of $350,000.

PHS policy requires that investigators make unique research resources available for research purposes to qualified individuals within the scientific community when they have been published (see the NIH Grants Policy Statement at http://grants.nih.gov/ grants/guide/notice-files/not96-184.html). In addition, NIH recently released a statement on the sharing of research data that applies to all investigator-initiated applications with direct costs greater than $500,000 in any single year (http://grants.nih.gov/grants/guide/ notice-files/NOT-OD-03-032.html).

All applicants who respond to this PAS must propose plaits for sharing data and biomaterials generated through the grant. Applicants should explain how funds for the storage and distribution of data and biomaterials will be obtained, and may request such funds in the budget of the application. It is expected that the data to be shared will be clinical, diagnostic, and pedigree structure information, and information about the genetic backgrounds and phenotypes of mutant or transgenic animal strains. Biomaterials to be shared will include patient DNAs and cell lines, and mutant or transgenic animal strains. When possible, data and biomaterials should be placed in databases or repositories that will permit their efficient distribution to investigators throughout the scientific community. An example of such a facility is the NINDS Human Genetics Resource Center (http://locus.umdnj.edu/ninds).

The Initial Review Group will evaluate the proposed sharing plan and comment on its adequacy in an administrative note in the summary statement. Reviewers will not Factor the proposed data-sharing plan into the determination of scientific merit or priority score. The adequacy of the plan will be considered by NIH staff in determining whether the grant shall be awarded. The sharing plan as approved, after negotiation with the applicant when necessary, will be a condition of the award.

Our understanding of pathogenic mechanisms in VCI would benefit tremendously from the use of standardized criteria for diagnosing this condition, including standardized methods for measuring cognitive function. NINDS plans to encourage and coordinate the use of a minimal diagnostic dataset in studies funded by ibis PAS. Until such a dataset is defined, applicants to this PAS should provide detailed descriptions of the patient data to be collected, including methods for independently assessing the presence and type of cerebrovascular disease, and levels of cognitive function. Rationale for choice of specific cognitive test(s) should be included. In addition, plans should be included for entry of disease and cognitive phenotypic data into a computerized database that may be easily shared with other researchers.

Applicants to be funded trader this PAS will be expected to travel to NIH once a year to share progress with NIH program staff; other investigators funded under this PAS, and additional advisers as deemed necessary by NIH program staff. Applicants should include funds to support one trip per year to Bethesda, MD (for the principal investigator and co-principal investigators only).

Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for federal grants or cooperative agreements. The D&B number can be obtained by calling 866-705-5711 or through the web site at http://www.dunandbradstreet.com/. The D&B number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 is available at http://grants.nih.gov/grants/funding/pbs398/ phs398.html in an interactive format. For further assistance contact GrantsInfo, 301-435-0714, email: GrantsInfo@nih.gov. The title and number of this PA must be typed on line 2 of the face page of the application form and tire YES box must be checked.

Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one package to: Center for Scientific Review, National Institutes of Health (NIH), 6701 Rockledge Drive, Room 1040, MSC 7710, Bethesda, MD 20892-7710 USA; Bethesda, MD 20817 (for express/courier service).

Applications must be mailed on or before the receipt dates described at http://grants.nib.gov/ grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PAS that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an unfunded version of an application already reviewed, but such application must include an introduction addressing the previous critique.

Contact: Gabrielle G. Leblanc, Program Director, Neurogenetics, National Institute of Neurological Disorders and Stroke (NINDS), Neuroscience Center, Suite 2136, MSC 9537, Bethesda, MD 20892-0001 USA, 301-496-5745, fax: 301-402-1501; e-mail: leblancg@ninds.nih.gov; Creighton H. Phelps, Director, Alzheimer's Disease Centers Program, Neuroscience and Neuropsychology of Aging, National Institute on Aging (NIA), National Institutes of Health, 7201 Wisconsin Ave., Suite 350, Bethesda, MD, 20892-0001 USA; 301-496-9350, Fax: 301-496-1494; email: phelpsc@nia.nih.gov; Stephen S. Goldman, Vascular Biology Research Program, Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute (NHLBI), 6701 Rockledge Drive, Suite 10192, MSC 7956, Bethesda, MD 20892-0001 USA, 301-435-0560, fax: 301-480-2858, e-mail: goldmans@nhlbi.nih.gov.

Reference: PA No. PAS-04-149
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Title Annotation:Fellowships, Grants & Awards
Publication:Environmental Health Perspectives
Date:Nov 15, 2004
Words:2512
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