Karen K. Miller - US grants

female; pituitary gonadal axis; hypopituitarism; endocrine disorder; androgens; hypogonadism; disease /disorder proneness /risk; cardiovascular disorder; biomarker; hormone regulation /control mechanism; clinical research; women's health; blood chemistry; human subject;

leptin; gonadotropins; dietary lipid; hormone regulation /control mechanism; menstrual cycle; menstrual cycle disorder; caloric dietary content; body composition; clinical research; human subject; nutrition related tag; women's health; female;

osteopenias; amenorrhea; oral contraceptives; bone metabolism; endocrine disorder; hypothalamus; biomarker; endocrine pharmacology; clinical research; female; human subject;

DESCRIPTION (adapted from the application) Anorexia nervosa is becoming increasingly common among young women. Osteopenia is a severe, frequent and often permanent comorbid medical complication of anorexia nervosa which results in debilitating vertebral crush fractures. The pathophysiology of the bone loss is incompletely understood, and no effective therapy exists. The osteopenia that occurs in this population is unique and differs from that of postmenopausal osteoporosis. Data of surrogate markers of bone turnover have shown decreased bone formation in addition to increased resorption seen in states of estrogen deficiency. Our preliminary data demonstrate that women with anorexia nervosa have a relative deficiency of the anabolic hormone testosterone which is known to stimulate bone formation in vitro. We hypothesize that testosterone deficiency, primarily of ovarian origin, contributes to the decreased bone formation and bone density seen in anorexia nervosa. This hypothesis will be tested by investigating whether administration of a physiologic replacement dose of testosterone increases bone formation and bone density in this population. In the first phase of this proposal we plan to investigate the prevalence and pathogenesis of androgen deficiency in women with anorexia nervosa and specifically to determine whether ovarian or adrenal androgens are reduced. In the second phase of the study we will investigate the metabolic effects of testosterone deficiency compared with testosterone repletion on bone markers by randomizing women with anorexia nervosa and testosterone deficiency to receive a physiologic replacement dose of testosterone or placebo for 12 weeks and measuring changes in bone turnover markers. In the third phase of the study, we will examine the effects of administering testosterone on bone density and body mass.

CRISP; Computer Retrieval of Information on Scientific Projects Database; Dose; Fats; Fatty acid glycerol esters; Funding; GHN; Grant; Growth Hormone; Growth Hormone 1; Hormone Replacement Rx; Hormone replacement therapy; Institution; Investigators; NIH; National Institutes of Health; National Institutes of Health (U.S.); Obesity; Pituitary Growth Hormone; Population; Purpose; Recombinant Growth Hormone; Recombinant Pituitary Growth Hormones; Relative; Relative (related person); Research; Research Personnel; Research Resources; Researchers; Resources; Risk Marker; STH; Somatotropin; Somatotropin, Recombinant; Source; Testing; Therapeutic GH; United States National Institutes of Health; Visceral; Weight; Woman; adiposity; cardiac disease risk; cardiac disorder risk; cardiovascular risk; cardiovascular risk factor; corpulence; corpulency; corpulentia; growth hormone deficiency; hGHN; heart disease risk; heart disorder risk; obese; obese people; obese person; obese population; somatotropic hormone

CRISP; Clinical Trials; Clinical Trials, Unspecified; Computer Retrieval of Information on Scientific Projects Database; Fats; Fatty acid glycerol esters; Funding; GHN; Grant; Growth Hormone; Growth Hormone 1; Hormone Replacement Rx; Hormone replacement therapy; Institution; Investigators; NIH; National Institutes of Health; National Institutes of Health (U.S.); Obesity; Pituitary Growth Hormone; Population; Purpose; Research; Research Personnel; Research Resources; Researchers; Resources; STH; Somatotropin; Source; United States National Institutes of Health; Visceral; Woman; adiposity; cardiac disease risk; cardiac disorder risk; cardiovascular risk; cardiovascular risk factor; clinical investigation; corpulence; corpulency; corpulentia; hGHN; heart disease risk; heart disorder risk; obese; obese people; obese person; obese population; somatotropic hormone

? DESCRIPTION (provided by applicant): The scientific goal of this project is to investigate the role of relative growth hormone (GH) deficiency in the etiopathology of bone loss in obese men and women, and the mechanisms by which GH may affect bone microarchitecture and strength. The candidate is an Associate Professor of Medicine at Harvard Medical School and a faculty member at Massachusetts General Hospital who is deeply committed to and highly qualified for a career in patient-oriented research and to mentor new clinician investigators. She has an outstanding record of patient-oriented research (POR) and mentoring during the first K24 grant period. The career development goal of this K24 competitive renewal application is to support the candidate's continued professional development as a POR mentor of fellows and junior faculty with her long-term goal of developing independent POR researchers. The candidate's specific short-term mentoring objectives are: 1) to attract and train new trainees, 2) assist her current mentees to obtain K and R grant funding, to develop their own POR focuses and assist with all other aspects of transitioning to independent careers focused on POR, 3) acquire additional mentoring skills and 3) continue and expand teaching in courses that reach a large number of trainees interested in pursuing POR careers. The candidate's NIH grants will form the basis of research project support for trainees. The candidate has a record of leadership in mentoring on a national level and a successful track record of mentoring trainees in the Massachusetts General Hospital (MGH) Endocrine Fellowship program and trainees from a number of other departments. The institutional environment is outstanding at the MGH and Harvard Medical School, with an extremely strong Department of Medicine, a Clinical Translational Science Center grant through Harvard Medical School, and a Clinical Research Program at the MGH, all of which offer a myriad of didactic opportunities, facilities and support. The Department of Medicine has made a strong commitment to the candidate, including protected time and dedicated space. The Midcareer Investigator Award in Patient-Oriented Research is an ideal mechanism to ensure the necessary support to protect time for mentorship for this outstanding mentor, who otherwise would have to increase her clinical and administrative responsibilities, and to ensure the candidate's continued success as a mentor and clinical researcher.

DESCRIPTION (provided by applicant): Obesity is an important risk factor for osteoporosis and fractures. With the growing prevalence of obesity in the U.S., understanding the pathophysiology of bone loss in this population is of importance to public health. Growth hormone (GH) is a critical mediator of bone homeostasis and is markedly reduced in obesity. Our preliminary data suggest an important role for the GH/insulin-like growth factor 1 system in the pathogenesis of bone loss in obesity. The development of novel imaging techniques provides an opportunity to investigate the effects of GH on skeletal structure and strength, which will provide insights into the pathogenesis of obesity related bone loss. Understanding the pathophysiology of bone loss in obesity may help identify new treatment targets for this important complication. We have assembled a team of investigators with extensive experience in patient-oriented research in endocrinology and radiology to perform these investigations.

DESCRIPTION (provided by applicant): Major depressive disorder is a significant public health problem, disproportionately affecting women. Approximately 70% of patients do not respond or only partially respond to standard SSRI treatment despite adequate dosing. In our open-label pilot data, two-thirds of women with major depressive disorder who were resistant or partially resistant to antidepressants achieved a response to very low-dose, physiologic transdermal testosterone administration; one-third of women treated achieved remission after 8 weeks of therapy, with no hyperandrogenic side effects. We propose a collaborative, randomized, placebo-controlled trial to determine whether larger, multi-center trials are indicated to investigate whether low-dose testosterone is an efficacious and well-tolerated augmentation strategy in women with major depressive disorder and SSRI partial/nonresponse. We propose a collaborative, multidisciplinary study from two academic medical centers in order to increase sample size, accelerate recruitment and increase sample diversity.

? DESCRIPTION (provided by applicant): The postdoctoral research training program in Endocrinology and Diabetes at the Massachusetts General Hospital provides intensive research experience in basic or clinical investigation, complemented by a didactic component appropriate to the training goals. The trainees are primarily M.D.'s and M.D./Ph.D.'s who desire a career in investigative endocrinology and academic medicine, as well as Ph.D.'s who want further research training. The trainees are selected from a large applicant pool on the basis of prior academic and/or research achievement and evidence of strong commitment to a career in biomedical investigation. The Program director (J. Avruch) and the Associate Director (J. Florez) are senior and mid-career Physician-Scientists respectively who govern in conjunction with a committee of experienced endocrine scientists (Habener, Kronenberg, Crowley, Freeman, Grinspoon and Klibanski). The faculty consists of 42 active, well-funded scientists, whose interests range broadly across the subdisciplines of endocrinology and from clinical, bedside investigation to molecular mechanisms. The trainees are supervised closely by a primary faculty mentor, and interact extensively with junior faculty, who often serve as secondary mentors. An extensive program of didactic sessions complements the research activity. The training period is 2-4 years but may include several years additional experience at junior faculty status, so as to permit consolidation of skills and maximal competitiveness for independent support. The productivity of past trainees during training has been very high overall, as judged by the number and quality of trainee publications. Twenty seven of 44 program graduates since 2004 supported by this award remain in academia and ten are in the biotechnology/pharmaceutical industry. Among the 27 in academia, 7 have an R01 or equivalent (R21, DP2, U01 site PI), six others have K series award, and three have KL2/Medical Research Investigator Training awards from the Harvard CTSA. The facilities at the MGH are extensive, including an Institutional Clinical Research Support Program and over 50,000 square feet of modern laboratories dedicated to endocrine training faculty. This training grant is the central stabilizing financial element in this program, and is critical in enabling M.D. trainees to achieve careers in biomedical investigation.

PROJECT ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide; progression to non-alcoholic steatohepatitis (NASH) cirrhosis occurs in a subset of patients and is the second leading indication for liver transplantation in the United States. The factors leading to the development of NAFLD and progression to nonalcoholic steatohepatitis (NASH), including inflammation and fibrosis, are poorly understood. Moreover, there is a lack of effective therapies for these disorders. Studies in animals and humans suggest that estrogen deficiency may be an important mechanism underlying the development of NAFLD and progression to NASH. However, no prospective, randomized, placebo-controlled studies have examined the impact of estrogen administration on steatosis, inflammation or fibrosis in postmenopausal women with NASH. Our overall hypothesis is that low-dose, transdermal estrogen administration will decrease hepatic fat, inflammation and fibrosis in women with biopsy-proven NASH. Further, we will explore estrogen?s immune and metabolic effects in the liver, including changes at the single-cell level. Aim 1 will test the hypothesis that estradiol administration will decrease fibrosis, inflammation and steatosis in women with biopsy-proven NASH. Aim 2 will determine the impact of estrogen on intrahepatic metabolic pathways and on the transcriptional landscape of intrahepatic immune cells. We hypothesize that estrogen will decrease fibrogenesis, decrease hepatic de novo lipogenesis, and increase lipid beta oxidation. These hypotheses will be tested with a rigorously designed, double-blind, placebo-controlled study of the effects of low-dose transdermal estrogen replacement therapy in postmenopausal women with NASH. State-of-the-art liver imaging, liver biopsies, whole liver transcriptomics and unbiased single cell RNAseq by SeqWell will be leveraged to investigate these hypotheses. We have assembled a team of investigators with extensive research experience in endocrinology (Dr. Miller), NAFLD (Dr. Corey), liver imaging (Dr. Bredella), and hepatic immunology (Dr. Lauer), which is uniquely positioned to carry out this multi-disciplinary proposal. Elucidating the effects of low-dose, transdermal estrogen administration on liver fibrosis, inflammation and steatosis has the potential to further our understanding of this disease process and identify new therapeutic targets where few currently exist.