NIH GUIDE, Volume 21, Number 20, May 29, 1992


PA:  PA-92-82


P.T. 34


  Oral Diseases 

  Physiological Processes 



  Diagnosis, Medical 



National Institute of Dental Research




Sjogren's syndrome is one of the major causes of xerostomia, the most

common manifestation of salivary gland dysfunction.  The National

Institute of Dental Research (NIDR) supports studies to improve

knowledge of the development, structure, function, and diseases of the

salivary glands and to determine the influence of salivary constituents

on oral health.  Toward this end, the NIDR seeks to stimulate basic and

clinical research, research training, and manpower development in the

broad area of the epidemiology, etiology, pathogenesis, diagnosis, and

treatment of xerostomia, particularly in relation to Sjogren's





The Public Health Service (PHS) is committed to achieving the health

promotion and disease prevention objectives of "Healthy People 2000,"

a PHS-led national activity for setting priority areas.  This Program

Announcement (PA), Sjogren's Syndrome and Salivary Dysfunction, is

related to the priority area of oral health.  Potential applicants may

obtain a copy of "Healthy People 2000" (Full Report:  Stock No.

017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.

017-001-00473-1) through the Superintendent of Documents, Government

Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).




Applications may be submitted by domestic and foreign, for-profit and

non-profit organizations, public and private, such as universities,

colleges, hospitals, laboratories, units of State and local

governments, and eligible agencies of the Federal Government.  Domestic

applications may include international components.  Applications from

minority individuals and women are encouraged.  Special eligibility

requirements specified in the pertinent guidelines for the various

mechanisms available for support of this program must be met.  Foreign

institutions are not eligible for the First Independent Research

Support and Transition (FIRST) Award.




The mechanisms available for support of this program include the

traditional Research Project Grant (R01), the Program Project Grant

(P01), the FIRST Award (R29), the small grant (R03), the Postdoctoral

Individual Fellowship (F32), and Senior Fellowship (F33) Awards, and

the following career development awards:  the Modified Research Career

Development Award (K04), the Physician Scientist for Dentist Award

(K11), and the Individual Dentist Scientist Award (K15).






The importance of saliva in oral health has become increasingly

apparent in the expanding aged population.  Here, advances in medical

procedures and utilization of medication have been combined in an

effort to maintain the "quality of life."  However, a common sequela to

this effort is an increased prevalence of salivary dysfunctions.  The

most common clinical manifestation of salivary dysfunction is a

decreased output of secretion, termed "dry mouth" (hyposalivation,

xerostomia, or asialorrhea).  Clinically, dry mouth may vary from a

slight reduction in salivary flow with transitory inconvenience to a

total xerostomia with severe difficulties in speech, mastication,

swallowing, digestion, and concomitant physical and psychological

indisposition.  The major causes of xerostomia include local and

systemic disease, pharmacological agents, radiation therapy,

immunological disorders, menopause, and environmental pollution.

Hyposalivation may lead to qualitative and/or quantitative changes in

the protective salivary films or pellicles that coat hard and soft

tissues.  This loss of an enamel or cemental pellicle could result in

an increase in plaque-mediated diseases, namely, dental caries and

gingivitis, that ultimately result in tooth loss.  Alteration in

mucosal pellicle may make the oral soft tissues more susceptible to

desiccation and environmental insult, leading to colonization by an

opportunistic microflora.  The end result may be painful ulcerations

and/or local infections with a very sensitive mucous membrane, with

consequent difficulties in accepting dental prostheses.


There are, apparently, no available prevalence or incidence data to

describe the frequency of Sjogren's syndrome in any population.  It has

been estimated that in the United States there are, at minimum, two

million such patients--the vast majority being postmenopausal women.

Another two million undiagnosed victims are estimated to suffer with

the disease.  Some cases may develop during childhood.  About half of

the cases are primary; the remainder are secondary.  Similarly, there

are no accurate data describing the frequency of iatrogenic salivary

dysfunctions, especially those related to specific pharmaceutical use.

It has been suggested that over 400 drugs in the Physician's Desk

Reference result in salivary gland dysfunction.  This claim, however,

is often based on subjective and anecdotal information and not

objective evaluations of gland performance.  Specifically, detailed

epidemiologic data are required for the prevalence and incidence of

Sjogren's Syndrome and for various iatrogenic disorders.


The etiology and pathogenesis of Sjogren's syndrome are not clearly

understood.  Sjogren's syndrome is a chronic, multisystem, autoimmune

disorder.  The lesion in this disease is an immunologically mediated

inflammatory exocrinopathy that starts with periductal infiltration of

the salivary tissue by plasma cells and lymphocytes.  The glandular

acini atrophy and progressively disappear, being replaced by a dense

infiltrate of lymphocytes.  Sjogren's syndrome may be caused by T-cell

abnormalities or a deficiency of T lymphocytes and subsequent

overactivity of other lymphocytes and the production of autoantibodies.

Specific antinuclear antibodies, the SS-A (Ro) and SS-B (La)

antibodies, are found in Sjogren's syndrome and may have diagnostic

value in patients with unexplained parotid swelling or other features

such as renal and pulmonary lesions.  These antibodies may antedate

clinical evidence of Sjogren's syndrome by months or years.  Salivary

duct autoantibodies are another characteristic finding in this disease,

but it appears that these antibodies may be causally unrelated to the

duct damage.  Whether the apparent disturbance in immunoregulation in

Sjogren's syndrome is due to predominantly environmental or genetic

factors is unknown.  In addition to the existence of genetic

predisposition to Sjogren's syndrome, it appears that the two variants

(i.e., primary and secondary) of this disorder, though related, have

distinct differences in genetics.  Although the Epstein-Barr virus has

received, over the past decade, continued attention as one virus that

might possibly play a role in Sjogren's syndrome, a causal relationship

has not been proven.  It was recently reported that a newly discovered

human retrovirus (the human intracisternal A-type retroviral particle)

might be involved in Sjogren's syndrome and perhaps in a variety of

other autoimmune diseases.  The finding of this virus in relation to

Sjogren's syndrome is important and needs to be confirmed.  Many

investigators feel that estrogen may also be a factor since 90 percent

of those with this disease are women.


There is a real need for rigorous clinical trials to test the efficacy

and safety of various treatment regimens designed to correct or improve

specific salivary dysfunctions.  These include trials to improve

secretory capabilities of patients who retain functional gland

parenchyma (responder patients).  Pilocarpine is one

parasympathomimetic drug that has been extensively and rigorously

tested and that has been shown to be useful for many patients.  Other

pharmaceuticals that have been suggested to benefit responder patients

include bromhexine (bisolvin) and anethole-trithione (sialor).

Clinically, artificial salivas have served as a replacement modality

for individuals exhibiting hyposalivation and those lacking functional

glands (nonresponder patients).  For sale as an "over-the-counter"

item, artificial salivas have been traditionally formulated to

replenish particular functions of saliva such as lubrication,

viscosity, tissue hydration, surface tension, and/or antimicrobial

properties.  Currently available products appear to be less than ideal,

since their effects are of limited duration, and they may either have

an unpleasant taste or irritate the mucosa.  Since a clearly promising

saliva substitute does not yet exist, proposed studies would very

likely be of the pilot or screening type.  Additionally, it has been

suggested that active stimulation of salivary secretion during head and

neck radiation may reduce the iatrogenic salivary hypofunction

associated with this therapeutic procedure.  It would be useful to test

the utility of a proven, effective sialogogue, like pilocarpine, for

such preventive therapy.


Research Goals and Scope


Based on recommendations by the Dental Research Programs Advisory

Committee at its June 7-8, 1988 and April 7-8, 1992 meetings, the NIDR

"Broadening the Scope:  Long-Range Research Plan for the Nineties," and

the NIDR/Fogarty International Center Report on "International

Collaboration for Oral Health Research" (Philip J. Holloway, April

1989), applications are invited for research project grants (including

minority research supplements), program project grants, FIRST awards,

small grants, career development awards, and postdoctoral fellowships

in the broad area of the epidemiology, etiology, pathogenesis,

diagnosis, and treatment of xerostomia, particularly in relation to

Sjogren's syndrome.  Some examples of research areas of interest

include, but are not limited to:


o  Development of reliable epidemiological data on the prevalence and

incidence of salivary gland disorders, such as Sjogren's syndrome and

xerostomia related to systemic medications, particularly among target

populations such as the aged and others at high risk.


o  Further investigations on the etiology and pathogenesis of diseases

and conditions that cause xerostomia.  This research should include

development of sophisticated model systems (cell culture and transgenic

animals) to investigate normal cellular processes and those evident in



o  Development of improved methods, including more sensitive and

specific assays using saliva, to diagnose specific salivary gland



o  Development and improvement of treatments for salivary hypofunction,

including genetic manipulation and development of organoids.


o  Development of new sialogogues and improved, long-acting saliva



o  Development of methods to expand and improve function of residual

salivary gland tissue after destructive disease or therapy (e.g.,

radiation and chemotherapy to treat head and neck cancers).  This

research should include methods aimed at tissue repair and



o  Development of techniques for the preservation and transplantation

of salivary glands.








NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical

research grants and cooperative agreements are required to include

minorities and women in study populations so that research findings can

be of benefit to all persons at risk of the disease, disorder or

condition under study; special emphasis must be placed on the need for

inclusion of minorities and women in studies of diseases, disorders and

conditions which disproportionately affect them.  This policy is

intended to apply to males and females of all ages.  If women or

minorities are excluded or inadequately represented in clinical

research, particularly in proposed population-based studies, a clear

compelling rationale must be provided.


The composition of the proposed study population must be described in

terms of gender and racial/ethnic group.  In addition, gender and

racial/ethnic issues should be addressed in developing a research

design and sample size appropriate for the scientific objectives of the

study.  This information must be included in the form PHS 398 in items

1-4 of the Research Plan AND summarized in item 5, Human Subjects.

Applicants are urged to assess carefully the feasibility of including

the broadest possible representation of minority groups.  However, NIH

recognizes that it may not be feasible or appropriate in all research

projects to include representation of the full array of United States

racial/ethnic minority populations (i.e., Native Americans [including

American Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks,

Hispanics).  The rationale for studies on single minority population

groups must be provided.


For the purpose of this policy, clinical research is defined as human

biomedical and behavioral studies of etiology, epidemiology, prevention

(and preventive strategies), diagnosis, or treatment of diseases,

disorders or conditions, including but not limited to clinical trials.


The usual NIH policies concerning research on human subjects also

apply.  Basic research or clinical studies in which human tissues

cannot be identified or linked to individuals are excluded.  However,

every effort should be made to include human tissues from women and

racial/ethnic minorities when it is important to apply the results of

the study broadly, and this should be addressed by applicants.


For foreign awards, the policy on inclusion of women applies fully;

since the definition of minority differs in other countries, the

applicant must discuss the relevance of research involving foreign

population groups to the United States' populations, including



If the required information is not contained within the application,

the review will be deferred until the information is provided.


Peer reviewers will address specifically whether the research plan in

the application conforms to these policies. If the representation of

women or minorities in a study design is inadequate to answer the

scientific question(s) addressed AND the justification for the selected

study population is inadequate, it will be considered a scientific

weakness or deficiency in the study design and will be reflected in

assigning the priority score to the application.


All applications for clinical research submitted to NIH are required to

address these policies.  NIH funding components will not award grants

or cooperative agreements that do not comply with these policies.




Applications will be accepted on an indefinite basis in accordance with

the receipt, Initial Review Group, National Advisory Council and

earliest possible beginning dates specified in the pertinent

application kits.  The specific application forms and kits required in

this connection are available at most institutional business offices

and may be obtained from the Office of Grants Inquiries, Division of

Research Grants, National Institutes of Health, Westwood Building, Room

449,  Bethesda, MD  20892, telephone (301) 496-7441.  The application

form PHS 398 must be used for research projects (R01, R29, P01, and

R03) and the Career Development Awards (K07, K11, and K15).  The

application form PHS 416-1 must be used for fellowships (F32 and F33).

The YES box must be checked and the title and number of the

announcement must be typed in item 2a on the face page of the

application form PHS 398 (rev. 9/91).  In the case of fellowship

applications, the announcement title must be typed in item 3 on the

face page of form PHS 416-1 (rev. 7/88).


The completed original application form PHS 398 and five legible copies

must be sent or delivered to:


Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**


When using the PHS 416-1 fellowship application, submit the original

and two copies to the above address.




Applications will be assigned on the basis of established PHS referral

guidelines.  Applications will be reviewed for scientific and technical

merit by study sections of either the Division of Research Grants, NIH

or the NIDR, in accordance with the standard NIH peer review procedures

and the review criteria customary for the support mechanism selected.

Following scientific-technical review, the applications will receive a

second-level review by an appropriate national advisory council or





Applications recommended for further consideration will compete for

available funds with all other applications.  The following will be

considered in making funding decisions:


o  quality of the proposed project as determined by peer review

o  availability of funds

o  program balance among research areas of the announcement




Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.


Direct inquiries regarding programmatic issues to:


G.G. Roussos, Ph.D.

Director, Salivary Research and Oral Biology Centers Program

Extramural Program

National Institute of Dental Research

Westwood Building, Room 505

Bethesda, MD  20892

Telephone:  (301) 496-7884


Direct inquiries regarding fiscal matters to:


Ms. Theresa Ringler

Chief, Grants Management Office

Extramural Program

National Institute of Dental Research

Westwood Building, Room 518

Bethesda, MD  20892

Telephone:  (301) 496-7437




This program is described in the Catalog of Federal Domestic Assistance

No. 93.121.  Awards are made under authorization of the Public Health

Service Act, Title IV, Part A (Public Law 78-410, as amended by Public

Law 99-77788-158, 42 USC 241 and 285) and administered under PHS grants

policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This

program is not subject to the intergovernmental review requirements of

Executive Order 12372 or Health Systems Agency review.



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