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Istvan J. Merchenthaler, MD, PhD, DSc

Academic Title:

Professor

Primary Appointment:

Epidemiology & Public Health

Secondary Appointment(s):

Anatomy Neurobiology

Location:

Baltimor4e

Phone (Primary):

(410) 706-1350

Education and Training

MD degree: 1974, University of Medical School, Pecs, Hungary

PhD degree: 1986, Hungarian Academy of Sciences, Budapest, Hungary

DSc degree: 1992, Hungarian Aacdemy of Sciences, Budapest, Hungary

Dr Habil: 1996: Albert Szent-Gyorgyi Medical Auniversiity, Szeged, hungary

Biosketch

OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015)

BIOGRAPHICAL SKETCH

Provide the following information for the Senior/key personnel and other significant contributors.
Follow this format for each person.  DO NOT EXCEED FIVE PAGES.

NAME: Merchenthaler, István

eRA COMMONS USER NAME (credential, e.g., agency login): IMERCHENTHALER

POSITION TITLE: Professor

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)

INSTITUTION AND LOCATION

DEGREE

(if applicable)

 

Completion Date

MM/YYYY

 

FIELD OF STUDY

 

University Medical School of Pecs, Hungary

M.D.

1974

Medicine

Hungarian Acad. Sci, Budapest, Hungary

Ph.D.

1986

Neuroendocrinology

Hungarian Acad. Sci, Budagest, Hungary

D.Sc.

1992

Neuroendocrinology

Albert Szent-Gyorgyi University, Szeged, Hungary

D.Habil.

1997

Anatomy, Histology, Embryology, Neuroscience

 

 

 

 

A.         Personal Statement

The long-term goal of my research program is identify potential therapies for aged-related conditions/disorders, including meno- and andropausal hot flushes, infertility, and neurodegenerative diseases, like Parkinson’s disease (PD), Alzheimer’s disease (AD) and cerebrovascular stroke. These goals encompass conducting translational research that will yield outcomes with tangible benefits to patients. One of my long-term goals is to evaluate neuroprotection by pituitary adenylate cyclase-activating polypeptide (PACAP38) and its metabolically stable analogs in animal models of neurodegenerative diseases. Another goal is to develop brain-selective estrogen therapy utilizing pro-drug approach. A third goal is to develop therapies for advanced aged women to increase their fertility.   

I have been trained in anatomy/neuroendocrinology, with expertise in the key research areas necessary for this application. These include (but are not limited to) extensive expertise with several rodent models and techniques, including rodent surgeries (stereotaxic brain surgeries, endocrine- and reproduction-related surgeries), necropsies, histology, RT-PCR and in situ hybridization histochemistry, immunocytochemistry, and Western blot analysis. I have developed rodent models of focal and global ischemia, hot flush, and other aspects of female reproductive physiology and aging.

 I started my research career in Hungary and then continued at the University of North Carolina, Chapel Hill, the National Institute of Environmental Health Sciences, Research Triangle Park; Wyeth Research; and finally here at the University of Maryland, Baltimore. Following mapping most of the neuropeptides regulating anterior pituitary function, my interest turned toward women’s health, including menopausal symptoms with special emphasis on hot flushes and neurodegeneration, and the role of estrogen receptors in these conditions.

 In 1994, I joined a research Group at Wyeth Research as one of the Directors of the Women’s Health Research Institute. While at Wyeth, my goal was to develop selective estrogen receptor modulators with beneficial actions in the brain, particularly for the treatment of focal and global ischemia and hot flushes.My group provided the first description of the distribution and regulation of estrogen receptor-beta and neuroprotection by estrogen in stroke and general ischemia models.

In 2004, I came to the University of Maryland Baltimore. In the first couple of years, I concentrated on the development of a brain-selective estrogen therapy. In collaboration with Dr. Prokai at North Texas Health Science Center, we are pursuing a pro-drug approach to reach our goal. Our compound is the pro-drug of 17β-estradiol (DHED, based on its chemical name). It is converted to 17β-estradiol only in the brain by a brain-specific reductase, thus, it is free of effects in the periphery. Our goal is to develop DHED for clinical use both in peri- and menopausal women and andropausal men.

During the last few years, in addition to estrogen, my interests have also returned to PACAP as a potential therapy for several neurological disorders such as PD, Alzheimer’s disease (AD), traumatic brain and spinal cord injury, diabetic nephro- and neuropathy and cerebrovascular stroke. I have started an intense collaboration with Drs. Maderdrut and Coy at Tulane University and Dr. Paul Yarowsky at the University of Maryland Baltimore to explore the use of proteolysis-resistant PACAP analogs for neurodegenerative diseases such as PD.

In 2008 I started collaborating with Dr. Lori Bernstein to develop therapies for advanced aged women. As our hypothesis is that the elevated FSH levels are the primary reason for infertility, our efforts have been to use drugs that reduce FSH to levels, characteristic for young women.

As a PI, I have been awarded and successfully administered both university and federally funded projects.  This requires knowledge of the science and also staffing, budgeting and producing peer-reviewed publications. I am actively collaborating with other researchers at multiple universities, which has taught me the importance of good communications skills.

 

B.        Positions and Honors

Employment/Experience

1974-1986: Assistant Professor, Department of Anatomy, Medical School, Pécs, Hungary.

1981-1983: Visiting Scientist, Department of Cell Biology and Anatomy, University of North Carolina, Chapel Hill, NC

1984: Visiting Scientist, US-Japan Biomedical Research Laboratories, Tulane University, New Orleans, LA

1986-1988: Associate Professor Anatomy/Histology/Embryology, University Medical School, Pécs, Hungary

1988-1994: Section Head, Visiting Scientist, NIEHS/NIH, Research Triangle Park, NC

1994-2003: Director, Women’s Health Research Institute, Wyeth Research, Collegeville, PA

2003-2004: Distinguished Research Scientist, Women’s Health and Bone Institute, Wyeth Research, Collegeville, PA

2004-present: Professor, Department of Epidemiology, University of Maryland, Baltimore, MD

2004-present: Professor, Department of Anatomy and Neurobiology, University of Maryland, Baltimore, MD

 

Editorial Positions:

1994-1998:  Board Member, Endocrinology

2008-2012:  Board Member, Endocrinology

Reviewer:

Ad hoc reviewer for more than 20 scientific journals

Ad hoc reviewer for NIH/NIMH Study Sections, National Science Foundation, Alzheimer’s Association, the Hungarian Academy of Sciences, and NHMRC (Australia)

C.        Contributions to Science

1. Description of the distribution of hypophysiotropic neurons in the brain. These included luteinizing hormone-releasing hormone (LH-RH), corticotropin-releasing hormone (CRH), growth hormone-releasing hormone (GH-RH), and thyrotropin-releasing hormone. The chemical structure of these neuropeptides was identified in the late seventies and eighties. I was either the first, or among the first, to provide the descriptions of their distributions in the rat (LH-RH, CRH, GHRH, and TRH) or human (GHRH) brain.  Contrary to what was expected based on previous indirect evidence, it turned out that with the exception of GHRH, most of these neuropeptides were present not only in the hypothalamus but in many other brain areas not connected to the hypophyseal portal circulatory system, supporting the hypothesis that in addition to functioning as regulators of the anterior pituitary gland (hypophysiotropic factors), they also function as neuromodulators. As the first author, I generated the ideas and completed the bulk of the work described in these publications.

Related references:

       1. Merchenthaler, I., Vigh, S., Petrusz, P., and Schally, A.V.: Immunocytochemical localization of corticotropin-releasing factor (CRF) in            the rat brain. Am. J. Anat. 165: 385‑396, 1982. PMID 6760710 (PMC number not available)

       2. Merchenthaler, I., Vigh, S., Schally, A.V., and Petrusz, P.: Immunocytochemical localization of growth hormone-releasing factor                     (GHRF) in the rat hypothalamus. Endocrinology 114:1082‑1085, 198. PMID: 6423368 (PMC number not available)

       4. Merchenthaler, I., Csernus, V., Csontos, C., Petrusz, P., and Mess, B.: New data on the immunocytochemical localization of                          thyrotropin-releasing hormone (TRH) in the rat central nervous system.  Amer. J. Anat. 181: 359‑376, 1988. PMID: 3133939 (PMC                  number not available)

       5. Merchenthaler, I.: Neurons with access to fenestrated capillaries in the central nervous system of the rat. Neuroscience 44:655-662,            1991. PMID: 1721686 (PMC number not available)

 2. Description of the connectivity of hypophysiotropic neurons and their interaction with other neuropeptides in the human hypothalamus. This work started almost twenty years ago when I convinced one of my young colleagues in Hungary to start working on his project. The project is still continuing and we have published yearly on this research topic. Our data confirms, or in some cases does not support, the data obtained from rodents and, thus, emphasize the importance of species differences in the distribution and connectivity of neurons synthesizing hypothalamic peptides.  These morphological data provide the basis of many physiological and pharmacological studies in humans. My roles in these publications were collaborator and advisor.

 Related references:

        1. Dudas, B and Merchenthaler, I.: Catecholaminergic axons innervate LH-releasing hormone immunoreactive neurons of the human                diencephalon. J. Clin. Endo. Metab. 86(11):5620-5626, 2001. PMC1701744

        2. Dudas, B and Merchenthaler, I.: Close juxtapositions between luteinizing hormone-releasing hormone synthesizing neurons and                   corticotropin-releasing factor-immunoreactive axons in the human diencephalon. J. Clin. Endo. Metab. 87:5778-5784, 2002.                           PMC12466386

        3. Dudas, B., Baker, M., Rotoli, G., Grignol, G., Bohn, M.C., Merchenthaler, I.:  Distribution and morphology of the                                           catecholaminergic neuronal elements in the human hypothalamus. Neuroscience, 17:187-195, 2010. PMC20801195

       4.  Merchenthaler, I., Rotoli, G., Peroski, M., Grignol, G., Dudas, B.: Catecholaminergic system innervates galanin-immunoreactive                  neurons in the human diencephalon. Neuroscience, 238:327-334, 2013. PMC23415787

 3. First description of the co-localization of LHRH and co-localization of galanin and dopamine and enkephalin in the rat brain. The co-localization of LHRH and galanin is estrogen-dependent and sexually dimorphic. The co-localization of dopamine and enkephalin is prolactin-dependent.  These findings contributed to the re-evaluation of our concept on Dale’s principles and provided an impetus for drug development. I generated the ideas, completed the bulk of the work and served as the first author, or I served as a co-investigator for these publications.

 Related references:  

  1. Merchenthaler, I., López, F.J. and Negro-Vilar, A.: Colocalization of galanin and luteinizing hormone-releasing hormone in a subset of preoptic hypothalamic neurons: Anatomical and functional correlates. Proc. Natl. Acad. Sci. USA 87:6326-6330, 1990. PMC54526
  2. López, F.J., Merchenthaler, I., Ching, M., Wisniewski, M. and Negro-Vilar, A.: Galanin: a hypothalamic hypophysiotropic hormone regulating reproductive functions. Proc. Natl. Acad. Sci. USA. 88:4508-4512, 1991. PMC51690
  3. Merchenthaler, I., Lennard, D., Negro-Vilar, A.: Neonatal imprinting predetermines the sexually-dimorphic estrogen-dependent expression of galanin in LHRH neurons. Proc. Natl. Acad. Sci. USA 90:10479-10483, 1993. PMC47800
  4. Merchenthaler, I.: Induction of enkephalin in tuberoinfundibular dopaminergic neurons during lactation. Endocrinology 133:2645-2651, 1993. PMID: 7694844 (PMC number not available)

 4. First description of the distribution of estrogen receptor-b in rodents and the role of estrogen receptors in ischemic brain injury. Our in vivo binding data with 3H estradiol suggested before the discovery of ER-β that another estrogen receptor exists in the brain. The distribution of ER-α was more restricted and different different than that of binding. The discovery of ER-β then explained many effects of estrogen that could not be explained by the distribution of ER-a, including the effect of estrogen on learning and memory (presence of ER-b in the neocortex and hippocampus) and depression/anxiety (presence of ER-b in the raphe nuclei). In addition the first report on the distribution of ER-β, we provided the first report on the critical role of ER-a-mediated neuroprotection in stroke models (focal cerebral ischemia). As the senior author in the publications below, I generated the idea and also participated in the laboratory work. One of our publications on ER-b (reference a below) has been cited over 1,700 times.

 Related references:

  1. Shughrue, P.J., Lane, M.V., Merchenthaler, I.: Comparative distribution of estrogen receptor-alpha and ER-beta mRNAs in the rat central nervous system. J. Comp. Neurol. 388:507-525, 1997. PMID: 9388012 (PMC number not available)
  2. Shughrue, P.J., Lane, M.V., Lubahn, D., Negro-Vilar, A., Korach, K., Merchenthaler, I.: Estrogen responses in the brain of estrogen receptor-disrupted mice. Proc. Natl. Acad. Sci. USA 94:11008-11112, 1997. PMC23564
  3. Dubal, D.B., Zhu, J., Rau, S.W., Shughrue, P.J., Merchenthaler, I., Kindy M.S., Wise, P.M.: Estrogen receptors alpha, not beta, is a critical link is estradiol-mediated protection against brain injury. Proc. Natl.  Acad. Sci. USA 98:1952-1957, 2001. PMC293637
  4. Merchenthaler, I., Hoffman G.E, Lane, M.V.: Estrogen and estrogen receptor-beta (ERβ) ligands stimulate galanin gene expression in luteinizing hormone-releasing hormone-immunoreactive (LHRH-i) neurons in the female rat. Endocrinology 146:2760-2765, 2005. PMID: 15790727 (PMC number not available)

 5. Development of a brain-selective estrogen therapy utilizing a pro-drug approach. In collaboration with Dr. Laszlo Prokai, a medicinal chemist at the North Texas health Science center, Fort Worth, TX, who discovered an intracellular redox cycle and DHED (pro-estrogen), we evaluated the beneficial effect of DHED in menopausal and andropausal symptoms, including hot flushes, depression, and learning and memory. I started to work on hot flushes while at Wyeth Research. I have modified (optimized) the original morphine-dependent rat hot-flush model and made it suitable for drug discovery. I have also developed a telemetric model approach to measure tail skin temperature and identified its estrogen-dependent circadian rhythm. The brain-selective estrogen therapy is a novel and innovative approach that prevents all the peripheral side effects (breast and uterine hypertrophy or cancer, and blood clot formation) of the current estrogen therapies. Our findings now are in press in Science Translational Medicine. My role is to coordinate and conduct most of the biological (e.g., hot flush quantification and gene expression profiling) studies.

 Related references:

       1. Prokai, L., Nguyen, V., Szarka, S., Garg, P., Sabnis, G., Bimonte-Nelson, H.A., McLaughlin, K.J., Talboom, J.S., Conrad, C.D.,                           Shughrue, P.J., Gould, T.D., Brodie, A., Merchenthaler, I., Koulen, P., Prokai-Tatrai, K. “The bioprecursor prodrug 10β,17β-                           dihydroxyestra-1,4-dien-3-one delivers 17β-estradiol selectively to the female brain,” Sci. Transl. Med.,297,ra113, 2015.

       2. Merchenthaler, I.,  Lane, M.V.,Sabnis, G., Brodie, A., Nguyen, V., Prokai, L., Tatrai-Prokai, K.: Treatment with aan orally v                           bioavailable prodrug of 17β-estradiol alleviates hot flushes without hormonal effects in the periphery. Nature, Scientific Reports,                     6:30721, 2016.

 List of Published Works in MyBibliography:

http://www.ncbi.nlm.nih.gov/sites/myncbi/1XYgakNTOtW5g/bibliography/48071454/public/?sort=date&direction=ascending

D. Research Support

Ongoing Research Support

R21AG050900-02                               Merchenthaler/Urbanszki (MPI)                                   04/15/2016-03/31/2018           1.2 calendar

Establishment of a primate model for menopausal hot flushes

This project will establish a non-human primate model to measure hot flushes with the non-invasive infrared technology

Role: PI (MPI)

 

5 K12 HD43489-5                     Tracy (PI)                                                                               01/09/2012-08/31/2017           1.2 calendar

NIH/NICHD

Maryland’s Organized Research Effort in Women’s Health (MORE-WH)

This project will provide interdisciplinary mentored training in women’s health research to junior faculty scholars in an effort to foster the expansion of women’s health research across a variety of disciplines.

Role: Research Director

 

HD 1U01 HD066435               Hoffman (PI)                                                                               01/08/2016-31/07/2-17            1.5 calendar

Kisspeptin Regulation and GPR54 Signaling in Reproduction

This project will explore the connectivity of the neuronal system regulating the activity of kisspeptin which

plays a critical role in the central regulation of reproduction. My role is to perform stereotaxic surgeries,

retrograde and anterograde labeling  and train postdocs for these technologies

Role: Co-investigator

                       

NIH, SBIR                               Ngyuen (PI)                                                                                  01/08/2016-07/31/2017           1.0 calendar

A novel remedy of hot flushes for breast cancer patients undergoing aromatase inhibitor therapy

Direct costs: $45,150              Indirect Costs: $24,155

Role: PI of subcontract

 

Completed Research Support

 

3R01AG031535-01A2S1        Merchenthaler (PI)                                               `                            09/30/2009 - 02/28/2012        

NIH/NIA

Novel treatment of menopausal hot flushes with para-quinol of estrogen.

To study if para-quinol of estrogen prevents depression/anxiety and sleep disturbances in animal models.

Role: PI

 

1RO1AG031535-01A2            Merchenthaler (PI)                                                                               07/01/2008 - 6/30/2012                    

NIH/NIA                                                                                                                                                                                                          

Novel treatment of menopausal hot flushes with para-quinol of estrogen.

The main goal is to determine whether para-quinol of estrogen prevents hot flushes in animal models.

Role: PI

 

5 K12 HD43489-5                     Langenberg  (PI)                                                                                01/09/2008 - 08/31/2013        

NIH/NICHD

Maryland’s Organized Research Effort in Women’s Health (MORE-WH)

This project will provide interdisciplinary mentored training in women’s health research to junior faculty scholars in an effort to foster the expansion of women’s health research across a variety of disciplines.

Role: Program Director

 

5R21AG033864-02                 Merchenthaler (PI)                                                                              04/01/2012 - 03/31/2014        

NIH/NIA

Hot flushes and SNPs of the norepinephrine and serotonin transporter genes

The main goal is to study the effects of these SNPs on the efficacy of SSRIs in alleviating hot flushes.

Role: PI

 

R21HD078077-01                               Wallen/Prokai/Merchenthaler (MPI)                                           08/05-2013-08/04/2015

Effects of brain-selective estradiol on gene expression and female sex behavior.

The purpose of this application is to collect preliminary data on the role of a CNS-selective estrogen on the female sex behavior of rhesus monkeys.

Role: PI (MPI)

 

 

Research/Clinical Keywords

Estrogen therapy, menopause, hot flushes, neuroprotection, neurodegeneration, PACAP38, infertility, animal models

Highlighted Publications

  1. Merchenthaler, I., López, F.J. and Negro-Vilar, A.: Colocalization of galanin and luteinizing hormone-releasing hormone in a subset of preoptic hypothalamic neurons: Anatomical and functional correlates. Proc. Natl. Acad. Sci. USA 87:6326-6330, 1990.

      2. Merchenthaler, I., Lennard, D., Negro-Vilar, A.: Neonatal imprinting predetermines the sexually-dimorphic estrogen-                                    dependent expression of galanin in LHRH neurons. Proc. Natl. Acad. Sci. USA 90:10479-10483, 1993. 

      3. Shughrue, P.J., Lane, M.V., Merchenthaler, I.: Comparative distribution of estrogen receptor-alpha (ER-a) and ER-beta (ER-b)

          mRNAs  in the rat central nervous system. J. Comp. Neurol. 388:507-525, 1997.

      4. Shughrue, P.J., Lane, M.V., Lubahn, D., Negro-Vilar, A., Korach, K., Merchenthaler, I.: Estrogen responses in the brain of estrogen                receptor-disrupted mice. Proc. Natl. Acad. Sci. USA 94:11008-11112, 1997.

      5. Dubal, D.B., Zhu, J., Rau, S.W., Shughrue, P.J., Merchenthaler, I., Kindy M.S., Wise, P.M.: Estrogen receptors alpha, not beta, is a               critical link is estradiol-mediated protection against brain injury. Proc. Natl., Acad. Sci. USA 98:1952-1957, 2001.

      6. Dudas, B and Merchenthaler, I.: Topography and associations of leu-enkephalin and luteinizing hormone-releasing hormone neurons

          in the human diencephalon. J. Clin. Endo. Metab.88:1842-1848, 2003.

      7. Bernstein, L.R., Mackenzie, A.C.L., Kraemer, D.C., Morley, J.E., Farr, S., Chaffin, C.L., Merchenthaler, I. Shortened estrous cycle

          length, increased FSH levels, FSH variance, and oocyte spindle aberrations and early declining fertility in aging senescence-accelerated           mouse prone-8 (SAMP8) mice: concomitant characteristics of human mid-life female reproductive aging. Endocrinology, 155:2287-

          3000, 2014.

      8Prokai, L., Nguyen, V.,  Szarka, Sz., Ughy, B., Sabnis, G., Bimonte-Nelson, H.A.,  McLaughlin, K.J., Talboom, J.S., Conrad, C.D.,

          Brodie,A., Gould, T.D., Koulen,P., Merchenthaler, I., Prokai-Tatrai, K. Metabolism-based targeting of 17β-estradiol into the brain.

          Science Translational Medicine, 7, 29,ra113, 2015.

      9. Merchenthaler, I., Lane, M., Sabnis, G., Brodie, A., Prokai-Tatrai, K.,  Prokai, L. Novel treatment of menopausal hot flushes with an                 estradiol bioprecursor in two animal models of thermoregulatory dysfunction. Nature, Scientific Reports, 6:30721, 2016.

 

Research Interests

During the first fifteen years of my research career, my work was focused on neuropeptides, especially peptides that regulate anterior pituitary function (i.e., hypophysiotropic hormones). Utilizing stereotaxic surgeries, retrograde labeling and immunocytochemistry, I provided the first descriptions of several of these peptide hormones. My PhD and DSc degrees were based on studies dealing with luteinizing hormone–releasing hormone (LHRH), corticotropin-releasing hormone (CRH), growth hormone-releasing hormone (GH-RH), thyroid-releasing hormone (TRH), and endogenous opioid peptides

Later, when I was at the National Institute of Environmental Health Sciences/NIH in Research Triangle Park, NC, I become interested in the co-localization of neuropeptides and the regulation of co-localization by sex hormones. These studies have led to the discovery of sex-specific and estrogen-dependent co-localization of LHRH with galanin in the preoptic area of the hypothalamus and the prolactin-dependent co-localization of enkephalins and dopamine in the tuberoinfundibular dopaminergic (TIDA) neurons. The work in this field has resulted in many publications in prestigious journals, including a few in the Proceedings of the National Academy of Sciences, USA. Although later my interest turned toward sex steroid hormones and their receptors (see below), I still have a lasting affection for neuropeptides.

In 1994, I joined Wyeth Research, a pharmaceutical company, as the Director of the Functional Morphology Division of the Women’s Health Research Institute. My primary activity was to support the discovery of novel tissue-selective estrogen therapeutics. My specific goal in this complex drug discovery process was to identify an estrogen receptor ligand that alleviates hot flushes in an animal model without stimulating the uterus and the breast. Besodeoxifen, which was discovered by our group, is such an estrogen receptor (ER) ligand; it is now available for menopausal women. However, we could not identify a brain- or central nervous system-specific estrogen.

While at Wyeth, a novel estrogen receptor (ER-beta) was discovered and we were among the first, and many times the first, scientists who provided the description of its distribution and the regulation of its synthesis in rodents. As we knew from animal models that estrogens provide neuroprotection in several neurodegenerative diseases and cerebrovascular stroke, my interest turned toward cerebrovascular stroke and its prevention/treatment with estrogen. Utilizing rodent models of stroke, in collaboration with Dr. Phylis Wise’s group at University of Kentucky, we showed that ER-alpha, the classical ER plays a critical role in neuroprotection.

 In 2004, I came to the University of Maryland, Baltimore (UMB) and started to teach again and continued my research. I have been collaborating with Dr. Laszo Prokai at North Texas Health Science Center, Fort Worth, TX who, while studying estrogen’s metabolism, has discovered an intracellular redox cycle by which estradiol, following scavenging free radicals, is converted to a steroid (DHED is its abbreviated name) which then is converted back to estrogen via a reductase that uses NADPH. This conversion takes place only in the brain. Therefore, DHED can be considered as a pro-estrogen and can be used as a pro-drug delivery approach for the brain. DHED is water soluble (i.e., drugable), does not bind to any receptors, and penetrates the blood-brain barrier with high efficacy. Once in the brain, it is converted to estradiol. My current effort focuses on developing a primate model of hot flush utilizing the non-invasive infrared imaging to measure changes in skin temperature. Development of such a model would give a boost for further research on DHED, addressing hot flushes. As many actions of testosterone in men are mediated via estradiol following the aromatization of testosterone to 17β-estradiol, DHED can be given to men to alleviate age-associated hypoandrogenic symptoms (hot flushes, depression, cognitive impairment, insomnia, and reduced libido) or similar symptoms in castrated men suffering from prostate cancer. 

My love for neuropeptides and neuroprotection has not ended. I strongly believe that complex diseases with specific chronological patterns of pathologic events such as Alzheimer’s disease, stroke, traumatic brain and spinal cord injuries, etc. cannot be cured or prevented by a single therapeutic that focuses on a single target/pathway. I am interested in exploring the therapeutic uses of pleiotropic treatment with estrogens or pituitary adenylate cyclase-activating polypeptide (PACAP). PACAP is a 38-amino-acid peptide and has remarkable anti-inflammatory and immunosuppressive activities. In addition, it has remarkable cytoprotective activities: it stimulates neurogenesis, induces the expression of DNA-repair enzymes, reduces edema, etc. Unlike other peptides, PACAP crosses the blood-brain barrier via a saturable uptake mechanism. In experimental stoke and traumatic brain and spinal cord injury models, PACAP provides neuroprotection hours after the injury. However, its half-life is short (4-6 minutes) and therefore, the native peptide is not practical to use as a therapeutic. To circumvent this problem, in collaboration with Drs. David H. Coy and Jerome L. Maderdrut of the Peptide Research Laboratory at Tulane University, we are going to evaluate novel, proteolysis-resistant, and receptor subtype-specific PACAP analogs with long half-lives in animal models of traumatic brain and spinal cord injuries and diabetic neuro- and nephropathies.

Another area where PACAP can be utilized is the chemotherapy-associated infertility. PACAP protects against the toxic effects of chemotherapeutic agents in granulosa cells of the ovaries and it is our hope that it will preserve the fertility of women under chemotherapy due to hematopoietic cancers or multiple sclerosis. The PACAP analogs will be tested as soon as our R21 applications, to be submitted in February, are funded. The Peptide Research Laboratory has been highly successful in translating basic peptide research into marketable medicines. It has developed two peptide-based drugs (triptorelin and lanreotide) that have been on the market in the U.S. and the European Union for over a decade.

Clinical Specialty Details

NA

Awards and Affiliations

NA

Grants and Contracts

Active:

R21AG050900-02         Merchenthaler/Urbanszki (MPI)              04/15/2016-03/31/2018       1.2 calendar

Establishment of a primate model for menopausal hot flushes

This project will establish a non-human primate model to measure hot flushes with the non-invasive infrared technology.

Role: PI (MPI)

 

5 K12 HD43489-5                       Tracy (PI)                               01/09/2012-08/31/2017  1.2 calendar

NIH/NICHD

Maryland’s Organized Research Effort in Women’s Health (MORE-WH)

This project will provide interdisciplinary mentored training in women’s health research to junior faculty scholars in an effort to foster the expansion of women’s health research across a variety of disciplines.

Role: Research Director

 

HD 1U01 HD066435                 Hoffman (PI)                             01/08/2016-31/07/2-17  1.5 calendar

Kisspeptin Regulation and GPR54 Signaling in Reproduction

This project will explore the connectivity of the neuronal system regulating the activity of kisspeptin which

plays a critical role in the central regulation of reproduction. My role is to perform stereotaxic surgeries,

retrograde and anterograde labeling  and train postdocs for these technologies

Role: Co-investigator

                            

NIH, SBIR                                Ngyuen (PI)                              01.08/2016-07/31/2017       1.0 calendar

A novel remedy of hot flushes for breast cancer patients undergoing aromatase inhibitor therapy

Direct costs: $45,150                 Indirect Costs: $24,155

Role: PI of subcontract

 

Completed Research Support

5P50NH103222-02                    Schwarz (PI)                              07/01/2015-06/30/2016   2.4 calendar

NIMH Silvio O. Conte Centers for Basic or Translational Mental Health Research (P50)               

Kynurenine acid and cognitive abnormalities in schizophrenia                  

The purpose of these studies is to study the role of kynurenic acid and metabolites of tryptophan in the pathogenesis of schizophrenia in humans and rodent models. My role is to study the expression of the genes associated with the kynurenine pathway with in situ hybridization histochemistry.

Role: Co-investigator

 

R21HD078077-01         Wallen/Prokai/Merchenthaler (MPI)        08/05-2013-05/31/2016  1.2 calendar

Effects of brain-selective estradiol on gene expression and female sex behavior.

The purpose of this application is to collect preliminary data on the role of a CNS-selective estrogen on the female sex behavior of rhesus monkeys.

Role: PI (MPI)

 

5R21AG033864-02                   Merchenthaler (PI)                     04/01/2011-06/31/2014   1.2 calendar

NIH/NIA

Hot flushes and SNPs of the norepinephrine and serotonin transporter genes

To study the effect of these SNPs on the efficacy of SSRIs in alleviating hot flushes.

Role: PI

 

5 K12 HD43489-5                     Langenberg (PI)                         01/09/2007-08/31/2012  1.2 calendar

NIH/NICHD

Maryland’s Organized Research Effort in Women’s Health (MORE-WH)

This project will provide interdisciplinary mentored training in women’s health research to junior faculty scholars in an effort to foster the expansion of women’s health research across a variety of disciplines.

Role: Program Director

 

1R01AG031535-01A2              Merchenthaler (PI)                     03/01/2009-02/28/2014  3.0 calendar           

NIH/NIA                                                                                                                                              

Novel treatment of menopausal hot flushes with para-quinol of estrogen.

To study if para-quinol of estreogen prevents hot flushes in animal models.

Role: PI (MPI)

 

3R01AG031535-01A2S1           Merchenthaler (PI)                     03/01/2009-02/28/2011  1.5 calendar

NIH/NIA

Novel treatment of menopausal hot flushes with para-quinol of estrogen.

To study if para-quinol of estrogen prevents depression/anxiety and sleep disturbances in animal models.

Role: PI

 

Maryland Industrial                   Merchenthaler (PI)                     08/01/10-07/31/11         0.12 calendar           

Partnership (MIPS) #4614         

Fertamax to prevent egg infertility

To study the effect elevated gonadotropin levels on chromosome structure and function

 

U54 HD36207                           Albrecht (PI)                             04/01/2004-03/31/2009  1.2 calendar

NIH

Studies of Female Fertility

The aims of this project are to study the effect of hormonal environment on the development of the

reproductive system.

Role: Co-I

 

R01 NS06-004                           Albuquerque (PI)                      01/91/2006-12/31/2007  1.2 calendar

NIH

Age and Sex Effects on Nerve Agent Damage to the Brain and Antidotal Therapies

This project will study the neuroprotective effect of galantamine on nerve agent-induced brain damage.

Role: Co-I

 

Pending – Principal Investigator:

R01, NIH                                  Merchenthaler/Prokai (MPI)

Brain-Selective Therapy to Alleviate Hot Flushes of Prostate Cancer Patients

The goal of the prpposed studies is to evaluate the utility of our brain-selective estrogen therapy in patients treated wityh aromatase inhibitors and as a result, suffer from menopausal symptoms.

Role: PI

Effort: 15%

 

R01, NIH                                  Albuquerque/Gullapalli/Merchenthaler/Pereira (MPI)

Targeting M1/M3 Muscarinic Receptors to Treat Gestational Pesticide Poisoning

Role: Co-investigator

Effort: 20%

 

R21AN3908177                        Merchenthaler (PI)

Prevention of chemotherapy-induced female infertility with PACAP in a mouse model

Role; PI

Effort: 10%

 

R21AN 3908547                       Merchenthaler/Yarowsky (MPI)

Effect of PACAP on onset and progression of Parkinson’s disease in chronic models

Role PI (contact PI)

Effort; 10%

 

R21AN39008622                      Merchenthaler/Farah (MPI)

Prevention/treatment of diabetic peripheral neuropathy with PACAP analogs

Role: PI (contact PI)

Effort: 10%

 

In the News

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Community Service

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Professional Activity

Teaching (lectures and laboratory) Human gross Anatomy and Histology to medical students

Teaching (lectures and laboratory) Human gross Anatomy and Embryology to dental students

Co-Course Master: Biology of Aging, Gerontology Program

Occasional lectures on GPILS-623, 645, 641 programs

Lecturing on the menopause to Nursing School students

PhD Thesis Committees

Master Thesis mentor

BIRCWH Research Director and mentor

Lab Techniques and Equipment

Immunocytochemistry

In situ hybridization histochemistry

Animal models of hot flush, stroke, type 1 and type 2 diabetes