The long-term goal of this project is to study mechanisms of pituitary control of ovarian and bone function in aging women. Normal ovarian function is dependent on follicle-stimulating hormone (FSH), a pituitary derived heterodimeric glycoprotein consisting of a ?-and a ?-subunit. Both the subunits are glycosylated with two N- linked sugar chains in each subunit. This fully glycosylated form is designated FSH24. Glycosylation plays a major role in secretion, serum half-life and biological actions of FSH. It is known that glycosylation of pituitary gonadotropins is also estrous/menstrual cycle- and age-specific. Biochemical and physiological studies in several species have identified unique hypo-glycosylated variants consisting of sugar chains only in the ? but either one or none on the ? subunit. These are known as hypo-glycosylated FSH glycoforms and designated as FSH21, FSH18 or FSH15. Most importantly, the ratio of hypo- to fully-glycosylated FSH forms is found age- dependent, with high levels of fully-glycosylated variant predominantly present in peri/post-menopausal women and may contribute to the aging-associated bone loss. However, the distinct in vivo biological functions of these FSH glycoform variants are unknown in normal and aging ovarian and bone physiology. The central hypothesis is that glycosylation on FSH is an age-related switch that changes target tissue specificity from ovary to bone. This hypothesis will be tested using genetically engineered mouse models in two specific Aims.
In Aim 1, we will test ovarian development and function progressively with aging using Fshb null mice expressing individual glycosylated forms of FSH. This genetic strategy will allow us to test systematically the in vivo biological actions of each glycosylated hFSH variant in ovarian physiology in the absence of endogenous mouse FSH.
In Aim 2, first, we will use the FSH glycoform-expressing mice and test bone development as a function of aging. To unequivocally test the direct FSH actions on bone, in one approach, we will engineer mice in which Fshr will be selectively deleted in osteoclasts by a Cre-lox approach. We will develop a second line that permits creating temporal loss of FSH at desired times. Functional analyses with these genetically altered mouse models will identify distinct biological actions of FSH variants in vivo during ovarian aging and by extrapolation in human ovarian senescence. These novel mouse models will also allow us to directly test whether aging-associated bone loss is dependent on FSH ligand or FSH receptor-mediated signaling in osteoclasts in the bone. Our studies may unravel a novel phenomenon of age-dependent N-glycosylation switch on a pituitary glycoprotein hormone that results in alterations in target tissue specificity (ovary versus bone) and may potentially lead to new therapeutic options for intervention of bone loss in aging women.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG029531-09
Application #
9994173
Study Section
Special Emphasis Panel (ZAG1)
Project Start
2009-04-15
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
9
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Wichita State University
Department
Type
DUNS #
053078127
City
Wichita
State
KS
Country
United States
Zip Code
67260
Das, Nandana; Kumar, T Rajendra (2018) Molecular regulation of follicle-stimulating hormone synthesis, secretion and action. J Mol Endocrinol 60:R131-R155
Gilbert, Sara Babcock; Roof, Allyson K; Rajendra Kumar, T (2018) Mouse models for the analysis of gonadotropin secretion and action. Best Pract Res Clin Endocrinol Metab 32:219-239
Kumar, T Rajendra (2018) Extragonadal Actions of FSH: A Critical Need for Novel Genetic Models. Endocrinology 159:2-8
Roy, Sambit; Gandra, Divya; Seger, Christina et al. (2018) Oocyte-Derived Factors (GDF9 and BMP15) and FSH Regulate AMH Expression Via Modulation of H3K27AC in Granulosa Cells. Endocrinology 159:3433-3445
Kumar, T Rajendra (2018) Fshb Knockout Mouse Model, Two Decades Later and Into the Future. Endocrinology 159:1941-1949
Kumar, T Rajendra (2017) The SO(H)L(H) ""O"" drivers of oocyte growth and survival but not meiosis I. J Clin Invest 127:2044-2047
Romereim, Sarah M; Summers, Adam F; Pohlmeier, William E et al. (2017) Gene expression profiling of bovine ovarian follicular and luteal cells provides insight into cellular identities and functions. Mol Cell Endocrinol 439:379-394
Liu, Peng; Ji, Yaoting; Yuen, Tony et al. (2017) Blocking FSH induces thermogenic adipose tissue and reduces body fat. Nature 546:107-112
Wang, Huizhen; Hastings, Richard; Miller, William L et al. (2016) Fshb-iCre mice are efficient and specific Cre deleters for the gonadotrope lineage. Mol Cell Endocrinol 419:124-38
Wang, Huizhen; May, Jacob; Butnev, Viktor et al. (2016) Evaluation of in vivo bioactivities of recombinant hypo- (FSH21/18) and fully- (FSH24) glycosylated human FSH glycoforms in Fshb null mice. Mol Cell Endocrinol 437:224-236

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